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Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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9
HYDRAZINES AND NITRIC ACID

This chapter discusses the committee’s review and evaluation of epidemiologic studies and toxicologic information on persistent human health effects that might have resulted from exposure to hydrazines and nitric acid (HNO3). This format is a departure from previous chapters in which the number of epidemiologic studies on exposure to fuels and combustion products were too numerous to include all in one chapter.

US military personnel present in the Persian Gulf region during Operation Desert Storm might have been exposed to inhibited red fuming nitric acid (IRFNA) and possibly unsymmetrical dimethylhydrazine (UDMH) if it was used as rocket fuel when they were near disintegrating incoming short-range ballistic missiles, commonly known as Scuds, that dispersed uncombusted fuel, oxidizers, and combustion products (DOD 2001). Somewhat fewer than 100 Scuds were launched by Iraq; about 50 were directed at Kuwait and the remainder came down in or near Israel (DOD 2001). Many of the Scuds broke apart on re-entry, each releasing about 300 lb of residual oxidizer and 100 lb of fuel (DOD 2001). Disintegration would have had to occur less than 3 km above the ground for those chemicals not to have been dissipated by the time they reached the ground (DOD 2000). If the chemicals did reach the ground, they could potentially expose an area of 2–3 km by 100–200 m but would evaporate within a few hours (DOD 2000). The National Research Council (NRC 1998) noted that in the vicinity of a rocket launch, nitric acid would be more likely to be in the form of an aqueous aerosol than a gas. The amount of nitric acid that would result if an ignited launch were aborted would greatly exceed the amount produced if combustion proceeded.

Military personnel in the vicinity of incoming Scuds reported experiencing an array of acute health effects, including burning sensations, tearing eyes, runny noses, nausea, vomiting, dizziness, sleeplessness, headaches, and blurred vision (DOD 2001). After aerial breakup of Scuds, “some cases” required medical treatment or hospitalization, but there were no instances of pulmonary edema (DOD 2000). After direct contact with several Iraqi missiles captured at a storage facility, there were two or three cases of skin burns (DOD 2001). The committee is not aware of other uses of hydrazines or nitric acid during the Gulf War that might have resulted in exposure of US military personnel.

Hydrazines have similar chemical structures but they differ in their production, uses, and adverse health effects (ATSDR 1997). Symmetrical (or 1,2-) dimethylhydrazine will not be considered here, because it is not used as a rocket propellant, as are hydrazine,

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

monomethylhydrazine (MMH), and unsymmetrical (or 1,1-) dimethlyhydrazine. Although Iraq had apparently experimented with UDMH as a rocket fuel, it is more likely that kerosene was the rocket fuel used during the Gulf War (DOD 2001).

Nitric acid, probably in the form of IRFNA, was used as an oxidizer for the propellant in the Scuds (DOD 2000). Metal corrosion is inhibited if a halogen compound, such as hydrogen fluoride or iodine, is added to red fuming nitric acid (RFNA) (DOD 2000). The oxidizer’s color and fuming properties result from the high concentration of nitric acid, relative to nitrogen dioxide, in the liquid (EFMA 1997).

The remainder of this chapter contains the committee’s evaluation of the scientific literature on adverse, persistent health effects of hydrazines and nitric acid. It begins by reviewing toxicologic information on those chemicals, then reviews human studies related to whether persistent health effects might be associated with exposure to hydrazines and nitric acid, and finally presents the committee’s conclusions.

TOXICOLOGY

This section provides an overview of toxicologic information on two chemicals—UDMH and RFNA—that may have been dispersed over Gulf War veterans by disintegrating Scuds. Because toxicologic data on those chemicals are sparse, the findings on similar chemicals are also reviewed. Data on hydrazine and MMH are considered in addition to those on UDMH, and information on nitric acid in general is reviewed with the extremely limited data specifically on RFNA. For each of those sets of chemicals (hydrazines and nitric acids), the following information is presented: uses, physical and chemical properties, exposure limits recommended by national and international government bodies and organizations, toxicokinetic properties, summaries of experimental studies, and any evidence of genetic susceptibility and of interactions between the chemicals in question and other substances.

The committee’s approach was to use toxicity data, primarily from experimental animal studies, for background information and as supporting evidence. Therefore, an extensive review of toxicologic studies was not appropriate here. Several organizations—for example, the Agency for Toxic Substances and Disease Registry (ATSDR 1997), the International Agency for Research on Cancer (IARC 1974, 1999a, 1999b, 1999c) the National Institute for Occupational Safety and Health (NIOSH 1976), and the National Research Council (NRC 1996, 1998, 2000)—have conducted reviews of hydrazine- and nitric acid-related compounds. The reader is referred to those sources for more detailed reviews of the toxicologic data on the compounds.

Hydrazines

Hydrazines contain two nitrogen atoms joined by a single covalent bond. Hydrazine, UDMH, and MMH are used as rocket propellants. Hydrazine is also used for such applications as agricultural pesticides and water treatment (IARC 1999b). UDMH is also used for chemical syntheses, as an absorbent for acid gas, and as a plant-growth control agent (NRC 2000). MMH is also used as a chemical intermediate (NRC 2000). Some physical and chemical characteristics of hydrazines are listed in Table 9.1.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

TABLE 9.1 Chemical Identity and Selected Physical and Chemical Properties of Hydrazines and Nitric Acid

Properties

Hydrazine

MMH

UDMH

Nitric Acid

Synonyms

Diamine, diamide, anhydrous hydrazine, hydrazine base

Methylhydrazine

1,1-Dimethylhydrazine, dimazine, dimazin

Aqua fortis, azotic acid, hydrogen nitrate, nitryl hydroxide; white fuming nitric acid (WFNA, 97.5% HNO3), red fuming nitric acid (RFNA, 85% HNO3), concentrated nitric acid (CNA, 68–70% HNO3)

CAS registry no.

302–01–2

60–34–4

57–14–7

7697–37–2

Molecular weight

32.05

46.07

60.10

63.01

Chemical formula

N2H4

CH6N2

C2H8N2

HNO3

Color

Colorless

Colorless

Colorless

Colorless, yellowish, or reddish-brown

Physical state

Liquid

Liquid

Liquid

Liquid

Boiling point

113.5°C

87.5°C

63.9°C

83°C (WFNA)

121°C (CNA)

Melting point

2°C

−52.4°C

−58°C

−42°C (WFNA)

−38°C (monohydrate)

−18°C (trihydrate)

Solubility

Miscible with water and methyl, ethyl, propyl, and isobutyl alcohols; insoluble in chloroform and diethyl ether

Soluble in hydrocarbons; miscible with water and low-molecular-weight monohydric alcohols

Miscible with water, alcohol, ether, dimethyl formamide, and hydrocarbons

Miscible in water

Vapor pressure

14.1 mm Hg at 25°C

49.63 mm Hg at 25°C

157 mm Hg at 25°C

57 mm Hg at 25°C (WFNA)—49 mm Hg at 20°C (CNA)

Flash point

37.8°C (closed cup)

−8.33°C

−15°C (closed cup)

Not flammable

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Properties

Hydrazine

MMH

UDMH

Nitric Acid

Explosive limits

4.7–100% by volume in air

Not found

2–95% by volume in air

Not found

Disassociation constant

na

na

na

pKa<0

Conversion factor

1 ppm=1.31 mg/m3

1 mg/m3=0.76 ppm

1 ppm=1.88 mg/m3

1 mg/m3=0.53 ppm

1 ppm=2.5 mg/m3

1 mg/m3=0.41 ppm

1 ppm=2.6 mg/m3

1 mg/m3=0.38 ppm

NOTE: CAS=Chemical Abstracts Services; MMH=monomethylhydrazine; UDMH=unsymmetrical dimethylhydrazine; na=not applicable.

SOURCES: ATSDR (1997), EFMA (1997), IARC (1992, 1999b), NRC (1996, 2000).

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Exposure limits and carcinogenic classifications have been recommended for hydrazines by such organizations as ACGIH, ATSDR, the US Environmental Protection Agency (EPA), IARC, NRC, and the Occupational Safety and Health Administration (OSHA). Those limits and classifications are summarized in Table 9.2.

Toxicokinetics

Animal studies using inhalation, dermal, and oral exposures have been conducted on the absorption, distribution, metabolism, and excretion of hydrazines. The toxicokinetics of hydrazines appears to differ among animal species (ATSDR 1997), and there are differences in the metabolic pathways of hydrazine, UDMH, and MMH (ATSDR 1997).

Hydrazines are rapidly absorbed into the blood, and they and their metabolites are distributed to various tissues, such as the kidney, liver, lung, muscle, bladder, and pancreas (ATSDR 1997; Kaneo et al. 1984; Pinkerton et al. 1967). Plasma concentrations in male rats given UDMH subcutaneously at 50 mg/kg rapidly decreased after exposure, with a half-life of about 1 hour (Fiala and Kulakis 1981). UDMH was detectable in the blood of dogs within 30 sec of application (at 5–30 mmol/kg) to their shaved chests, but blood concentrations did not start to rise substantially for about 5 minutes (Smith and Clark 1971). Similar results were reported for cutaneous absorption of hydrazine (at 3–15 mmol/kg) (Smith and Clark 1972).

There does not appear to be preferential accumulation in specific tissues. Hydrazines with a free amino group are able to react with endogenous alpha-keto acids, which can produce adverse health effects (ATSDR 1997). Hydrazine undergoes acetylation and can react with cellular molecules in vivo (Kaneo et al. 1984; Llewellyn et al. 1986; Preece et al. 1991). UDMH undergoes demethylation and can react with cellular molecules (Mitz et al. 1962).

Evidence suggests that at least some hydrazines are metabolized by both enzymatic and nonenzymatic pathways (ATSDR 1997; Godoy et al. 1984; Tomasi et al. 1987). The metabolic process may be dose-dependent and saturable (Preece et al. 1992). Three cytochrome P450 isozymes (CYP2E1, CYP2B1, and CYP1A1/2) are involved in metabolism of hydrazine (Delaney and Timbrell 1995; Jenner and Timbrell 1994; Timbrell et al. 1982). Hydrazine has also been shown to be metabolized by another enzymatic pathway (peroxidases) and by a nonenzymatic pathway (a copper-ion-mediated pathway) (Sinha 1987). Hydrazine metabolism produces free radicals and carbonium ion intermediates that may be responsible for adverse health effects (ATSDR 1997). Koizumi et al. (1998) found that metabolism of hydrazine in humans is affected by genotypes of an isozyme of N-acetyltransferase, NAT2.

Hydrazines and their metabolites are excreted in urine and in expired air (ATSDR 1997). Llewellyn et al. (1986) reported that unchanged hydrazine, acetyl hydrazine, and diacetylhydrazine were found in the urine of hydrazine-treated animals.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

TABLE 9.2 Recommended Exposure Limits for Hydrazines and Nitric Acid

Organization

Chemical

Type of Exposure Limit

Recommended Exposure Limit

Reference

ACGIH

Hydrazine

TLV

0.01 ppm, A3, skin (adopted 1995)

ACGIH 2003

 

UDMH

TLV

0.01 ppm, A3, skin (adopted 1995)

ACGIH 2003

 

MMH

TLV

0.01 ppm, A3, skin (adopted 1995)

ACGIH 2003

 

Nitric acid

TLV

2.0 ppm (adopted 1976)

ACGIH 2003

 

Nitric acid

STEL

4.0 ppm

 

ATSDR

Hydrazine

MRL

0.004 ppm (intermediate-duration inhalation exposure)

ATSDR 1997

 

UDMH

MRL

0.0002 ppm (intermediate-duration inhalation exposure)

 

EPA

Hydrazine

Evaluation of carcinogenicity

Probably human carcinogen (group B2)

IRIS 2003

IARC

Hydrazine and UDMH

Evaluation of carcinogenicity

Overall evaluation: possibly carcinogenic in humans (Group 2B); sufficient evidence of carcinogenicity in experimental animals; inadequate evidence in humans

IARC 1999

 

Nitric acid (included in review of strong-inorganic-acid mists, in which exposure to sulfuric acid dominated most studies)

Evaluation of carcinogenicity

Overall evaluation: strong-inorganic-acid mists containing sulfuric acid are carcinogenic in humans (group 1); sufficient evidence from occupational exposures

IARC 1992

NIOSH

Hydrazine

REL

0.03 ppm

NIOSH 1997

 

 

IDLH

50 ppm

 

 

MMH

REL

0.04 ppm

 

 

IDLH

20 ppm

 

UDMH

REL

0.06 ppm

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Organization

Chemical

Type of Exposure Limit

Recommended Exposure Limit

Reference

 

 

IDLH

15 ppm

 

NIOSH

Nitric acid

REL

2.0 ppm

NIOSH 1994

 

STEL

4.0 ppm

 

IDLH

25 ppm

NRC

Hydrazine

SMAC

0.02 ppm (30-day exposure)

NRC 1996 2000

 

MMH

AEGL-2

0.11 ppm (8-hr exposure)

 

UDMH

 

0.38 ppm (8-hr exposure)

OSHA

Hydrazine

PEL

1.0 ppm

OSHA 1997 (29 CFR 1910.1000)

 

UDMH

 

0.5 ppm

Nitric acid

2.0 ppm

OSHA 1972 (29 CFR 1910.93)

NOTE: UDMH=unsymmetrical dimethylhyrazine; MMH=monomethylhydrazine; ACGIH=American Conference of Governmental Industrial Hygienists; TWA=time-weighted average; TLV=threshold limit value (TWA for 8-hr workday and 40-hr workweek); STEL=short-term exposure limit (TWA for 15 min); A3=confirmed animal carcinogen with unknown relevance to humans; skin=potentially large contribution to exposure by cutaneous route; ATSDR=Agency for Toxic Substances and Disease Registry; EPA=US Environmental Protection Agency; IARC=International Agency for Research on Cancer; NIOSH=National Institute for Occupational Safety and Health; OSHA=Occupational Safety and Health Administration; MR=minimal risk level; REL=recommended exposure limit (TWA for 10-hr workday during 40-hr workweek); IDLH=concentration immediately dangerous to life or health; AEGL-2=acute exposure guideline level 2; SMAC=spacecraft maximum allowable concentration; PEL=permissible exposure limit (TWA for 8-hr workday during 40-hr workweek).

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×
Experimental Studies

Experimental studies of the toxicity of hydrazines in humans and laboratory animals are summarized here. This section focuses on studies that examined chronic effects of hydrazines, particularly effects shown to persist after cessation of exposure. Epidemiologic studies assessing the adverse health effects of hydrazines are reviewed later in this chapter. On the basis of experimental data, chronic health effects of concern in relation to hydrazines are cancer and injuries to the respiratory tract, liver, and nervous and reproductive systems.

Respiratory Effects

MacEwen et al. (1970) exposed seven male volunteers (23–44 years old) to MMH at 90 ppm for 10 minutes by inhalation. The group consisted of smokers, former smokers, and nonsmokers. Acute effects included mild to moderate irritation of the nose, throat, and eyes; but there was no excessive lacrimation or coughing. No substantial exposure-related effects as measured with spirometry or clinical chemistry were observed during the 60 days after exposure, except for a 3–5% increase in Heinz body formation at day 7 that declined after 2 weeks.

Rats and mice exposed by inhalation to UDMH at as low as 0.05 ppm for 6 months showed effects on the lungs (hyperplasia) and nasal mucosa (inflammation, hyperplasia, and dysplasia) (Haun et al. 1984; Vernot et al. 1985). Dogs subchronically exposed at 25 ppm UDMH showed lung irritation and damage, but exposure at 5 ppm did not cause those effects (Rinehart et al. 1960). No studies that assessed respiratory effects after cessation of exposure of laboratory animals to hydrazines were found.

Hepatic Effects

Multiple hepatic effects have been observed in laboratory animals exposed to hydrazine and UDMH by inhalation and orally. Hepatotoxic changes (fatty changes, hyperplasia, hemosiderosis, increased serum enzymes, degeneration, and pigmentation of Kupffer cells) were observed in rats, mice, dogs, and monkeys subchronically or chronically exposed by inhalation to hydrazine at 0.25–14 ppm or to UDMH at 0.05–25 ppm (Comstock et al. 1954; Haun 1977; Haun and Kinkead 1973; Haun et al. 1984; House 1964; Rinehart et al. 1960; Vernot et al. 1985; Weatherby and Yard 1955). Oral exposure to hydrazine also caused hepatotoxic effects in rats, mice, and hamsters (Biancifiori 1970; Preece et al. 1992; Wakabayashi et al. 1983; Weatherby and Yard 1955).

Nervous System Effects

The nervous system appears to be a target for hydrazine and UDMH. Hydrazine has been used as a chemotherapeutic agent, and some cancer patients treated with hydrazine orally at 0.2–0.7 mg/kg/day experienced neurologic effects, such as nausea, vomiting, dizziness, excitement, lethargy, and neuritis (ATSDR 1997; Ochoa et al. 1975); the side effects subsided on cessation of treatment. Nervous system effects (such as tremors, vomiting, convulsions, lethargy, and behavioral changes) have been observed in rats, mice, and dogs repeatedly exposed to hydrazine at 1 ppm or UDMH at up to 140 ppm by inhalation and acutely exposed to hydrazine at 3–15 mmol/kg or UDMH at 5–30 mmol/kg) dermally (Haun and Kinkead 1973; Rinehart et al. 1960; Smith and Clark 1971, 1972; Weeks et al. 1963).

Reproductive and Developmental Effects

Keller et al. (1984) conducted a teratogenicity assessment of MMH and UDMH in rats with intraperitoneal administration but reported that developmental toxicity occurred only at

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

doses that were toxic to the dams. Reproductive effects (ovarian and testicular atrophy, endometrial inflammation, endometrial cysts, and aspermatogenesis) were observed in hamsters and mice exposed by inhalation to hydrazine at 1–5 ppm (Vernot et al. 1985) and UDMH at 0.05 ppm (Haun et al. 1984).

Cancer

A number of animal studies have reported increases in the incidence of cancers after exposure to hydrazines (reviewed in ATSDR 1997; IARC 1999b; NRC 1996, 2000). Studies of hamsters exposed to UDMH by subcutaneous injection have had both positive findings (Ernst et al. 1987) and negative findings (Jeong and Kamino 1993). Oral exposures (by gavage or in drinking water) to UDMH or hydrazine (administered as hydrazine sulfate or isonicotinic acid hydrazide), however, have produced increased tumor rates (particularly of respiratory or hepatic tissues) in multiple strains of mice, rats, and hamsters (Bhide et al. 1976; Biancifiori 1970; Biancifiori et al. 1964, 1966; Bosan et al. 1987; Maru and Bhide 1982; Roe et al. 1967; Severi and Biancifiori 1968; Steinhoff and Mohr 1988; Toth 1969).

Inhalation exposure, which would be most relevant to the Gulf War experience, has been less intensively investigated but also produced positive findings. Year-long exposure of rats and hamsters to hydrazine at 0.05, 0.25, 1.0, or 5.0 ppm for 6 hr/day, 5 days/wk followed by at least a year of observation before sacrifice led to dose-dependent increases in the incidence of lesions of the nasal epithelium (Vernot et al. 1985). Mice had slight increases in the incidence of lung adenomas in the high-dose group, but the small groups of dogs (four males and four females per dose level) showed no consistent response (Vernot et al. 1985). Inhalation exposure of rats and mice to UDMH was associated with leukemia and tumors of the lung, nasal passages, bone, pancreas, pituitary, blood vessels, liver, and thyroid (Haun et al. 1984). Chronic inhalation of MMH was not found to be carcinogenic in rats or dogs, but it did produce lung, nasal, and liver tumors in mice and nasal, renal, and adrenal tumors in hamsters (Kinkead et al. 1985).

Genotoxicity

Hydrazine and UDMH have been shown to be genotoxic in both in vivo and in vitro tests (reviewed in ATSDR 1997). Hydrazine and UDMH are alkylating agents and produced DNA damage in in vivo assays but had negative results in in vivo assays of unscheduled DNA synthesis, dominant lethal mutation, and gene mutation. Hydrazine and UDMH had positive results in gene-mutation assays in Salmonella typhimurium and Escherichia coli with and without activation and in Photobacterium leiognathi without activation. Mammalian cell assays had positive results for DNA alkylation, transformation, sister chromatid exchange, and unscheduled DNA synthesis without activation, and for gene mutation with and without activation.

Other Health Outcomes

Amyloidosis of the kidneys was observed in hamsters exposed to hydrazine by inhalation at 0.25 ppm for 6 hr/day, 5 days/wk for 1 year but not in rats, mice, or dogs experiencing the same treatment regimen (Vernot et al. 1985). No renal effects were observed in dogs exposed to UDMH by inhalation at 25 ppm (Rinehart et al. 1960) or in mice given hydrazine orally at 9.5 mg/kg/day (Steinhoff et al. 1990).

Case studies have suggested that exposure to hydrazine or hydrazine derivatives is associated with systemic lupus erythematosus or a similar syndrome (Durant and Harris 1980) (Pereyo 1986), but the data are too sparse to support conclusions about an association. In addition, decreased T helper-cell counts observed in mice given UDMH by injection at 75

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

mg/kg/day are inconsistent with an autoimmune response (Frazier et al. 1991). In other studies, lymphocyte activity and DNA synthesis were suppressed by in vitro exposure to UMDH, possibly because of effects on interleukin-2 production or intracellular calcium (Bauer et al. 1990; Frazier et al. 1992). Taken together, data from laboratory animal studies fail to provide biologic plausibility of the hydrazine-induced autoimmunity suggested by human case reports.

Hydrazine is a sensitizing agent. Multiple case studies have reported that dermal exposure to solutions containing up to 1% hydrazine causes contact dermatitis (reviewed in ATSDR 1997).

Genetic Susceptibility

Little is known about genetic susceptibility to toxic effects of hydrazines. In laboratory animals, susceptibility to hydrazines varies with species, strain, and age (ATSDR 1997; NRC 2000).

Interactions

No data were found on potential interactions between hydrazines and other chemicals.

Nitric Acid

In addition to its use as an oxidizer in explosives, nitric acid is used as a mineral acid in industrial processes (particularly in metal pickling and electroplating) and is a component in the manufacture of synthetic fertilizers (ACGIH 2003; IARC 1992; Sathiakumar et al. 1997).

Some physical and chemical characteristics of nitric acid are presented in Table 9.1. Naming conventions and several of nitric acid’s properties (particularly vapor pressure, melting and boiling points, and color) depend on the proportion of nitrogen dioxide (NO2) in the nitric acid solution. Reagent grade or “concentrated” nitric acid (CNA) contains about 70% nitric acid. The fuming property is associated with yet more concentrated mixtures, which contain correspondingly less nitrogen dioxide; red fuming nitric acid (RFNA) is about 85% nitric acid, and white fuming nitric acid (WFNA) is about 97.5% nitric acid (ACGIH 2003; EFMA 1997). The designation “inhibited” for the rocket-fuel oxidizers connotes the inclusion of halogen additives (about 1% hydrogen fluoride or iodine) to suppress the corrosive properties of nitric acid on metal equipment (DOD 2000). Nitric acid is not combustible, but it is dangerously reactive with many materials (EPA 1987).

The extreme corrosive potential of this strong acid has long been recognized. As summarized in Table 9.2, ACGIH adopted a TLV of 2 ppm for nitric acid in 1966 on the basis of case reports dating from 1804 and animal studies published in 1954 (Diggle and Gage 1954) (Gray et al. 1954b); this was supplemented by a short-term exposure limit (STEL) of 4 ppm in 1976. NIOSH recommended the same values in 1976, and the Occupational Safety and Health Administration (OSHA) adopted a permissible exposure limit (PEL) for nitric acid of 2 ppm. Authoritative review bodies have drawn their conclusions about nitric acid in large part on the basis of its likely mechanistic similarity to and co-occurrence in occupational mists with other strong inorganic acids (EPA 1987; IARC 1992; NIOSH 1976).

Toxicokinetics

Nitric acid has a corrosive effect upon contact with biological tissues. It produces oxides of nitrogen, particularly nitrogen dioxide, when it spontaneously decomposes or reacts with

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

metals or organic materials (NIOSH 1976). The deposition and toxicity of nitric acid in the respiratory tract is a function of the form of the nitric acid (vapor or aerosol); vapor or small particles penetrate more deeply into the lung. IARC (1992) noted that nitric acid is generally a vapor but that its water solubility when aerosol forms would favor upper airway deposition of larger particles that would have greater potential to alter the pH of mucus in a specific location. More recent investigations suggest that, contrary to expectation, inhaled vapor-phase nitric acid may be converted into or deposited on small particles in the humid atmosphere of the respiratory tract; this would facilitate its transport to and deposition in the deep lung (Chen and Schlesinger 1996). Detailed information on absorption, metabolic processing, tissue-specific distribution, or elimination of nitric acid was not found.

Experimental Studies

Experimental studies that address the toxicity of nitric acid in laboratory animals are summarized here. Epidemiologic studies assessing the adverse health effects of nitric acid are reviewed later. The primary concern of this chapter is effects of nitric acid that might persist after cessation of exposure.

The immediate consequences of contact with nitric acid are severe enough for its acute effects to have led to controlling its occupational use and to additional regulation; therefore, the chronic effects and toxic mechanism of nitric acid have not been extensively investigated with contemporary protocols. On the basis of case reports and experimental data, the chronic health effects of concern for nitric acid are the residual effects of irritation of the eyes, skin, respiratory tract, and gastrointestinal tract; dental erosion; and the possibility that it is carcinogenic.

Residual Effects of Corrosive Action and Irritation

Occupational case reports adequately document the severe and potentially permanent dermal and ocular damage that results from contact with nitric acid, so few animal studies of these effects have been conducted. Dermal contact with concentrated nitric acid can produce burns or severe irritant (acute eczematous) dermatitis, damaging the skin’s upper and lower layers within minutes and possibly resulting in permanent scarring and impairment of function (Birmingham 1988). Aside from burns, nitric acid may stain skin yellow to brown because of the conversion of skin proteins to xanthoproteic acid (White 1934). More dilute solutions produce milder irritation and hardening of the epithelium (NIOSH 1976).

Contact of the eye with nitric acid in sufficient amount or concentration can produce corneal opacification; mild injury may resolve, but severe ocular damage may persist as blindness (NIOSH 1976).

Case studies of workers exposed subchronically to vapors of nitric acid have consistently reported erosion of dental enamel, a permanent effect. Most often, however, such exposure occurs in combination with other strong acids, such as sulfuric or hydrochloric acid, which actually may be more potent than nitric acid in this respect (Dettling 1935; Lynch and Bell 1947; tenBruggen Cate 1968).

Similarly, the corrosive effects on the gastrointestinal tract and potentially lethal consequences observed in isolated cases of nitric acid ingestion have obviated the need for experimentation with animals on such outcomes (NIOSH 1976). In any event, this route of exposure would not be pertinent for Gulf War veterans exposed to nitric acid showering down from disintegrating Scud missiles.

Somewhat more toxicologic investigation has been conducted regarding the respiratory consequences of inhaling nitric acid vapors at various concentrations. The report by Diggle and

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Gage (1954) of exposure to nitric acid for an unspecified period at 25 ppm (63 mg/m3) as a no-observed-effect level (NOEL) in rats was first cited by ACGIH when proposing the current TLV of 2 ppm in 1964 and has since served as a primary piece of toxicologic data supporting regulatory levels for nitric acid; the original article, however, provided no detail about the conduct of the assay (NIOSH 1976).

The other long-referenced body of information about the toxicologic effects of inhaling nitric acid (and RFNA in particular) is a series of studies by Gray et al. (1952, 1954a, 1954b). Rats exposed to RFNA (nitrogen dioxide at 9–14 ppm, nitric acid concentration not stated) showed widespread inflammation of the airways, especially of the upper portion, immediately after exposure for 40–96 hours; several weeks later, much of the inflammation had abated, but all lungs examined were reported to have localized areas of “emphysema”. The extent and persistence of those effects were not functions of duration of exposure (Gray et al. 1952). Acute 30-minute exposures of male rats to nitrogen dioxide alone, RFNA (8–17% nitrogen dioxide), or WFNA (0.1–0.4% nitrogen dioxide) produced lethal concentrations (LC50s) of 174 ppm, 310 ppm, and 334 ppm, respectively; burns were observed on the animals, but pulmonary edema was the cause of death (Gray et al. 1954b). Those findings have been interpreted as suggesting that the nitrogen dioxide with which nitric acid coexists may be the primary toxic constituent of the vapor mixtures (ACGIH 2003; NIOSH 1976). Chronic exposure of 30 mice, 90 rats, and 10 guinea pigs to RFNA at 4 ppm for 4 hr/day, 5 days/wk for up to 6 months produced no pathologic changes compared with control animals (Gray et al. 1954a).

There have been several studies of nitric acid’s effect on isolated animal tissues (Greenberg et al. 1971; Pham-Huu-Chanh et al. 1966; Preziosi and Ciabattoni 1987). Nitric acid has been used to produce animal models of human obstructive airway disease (Greenberg et al. 1971; Mink et al. 1984; Peters and Hyatt 1986; Totten and Moran 1961).

More recently, nitric acid has been one of several components of ambient air pollution investigated in chamber studies. Nitric acid alone was found to penetrate far more deeply into the lung than might have been expected given its anticipated solubility in the mucus of the upper respiratory tract, perhaps as a result of being converted from vapor to particle form (Schlesinger et al. 1994, 1995). Nitric acid also impaired macrophage secretion of superoxide and tumor necosis factor alpha, and this has implications for pulmonary immunocompetence (Schlesinger et al. 1994, 1995) Unlike acid sulfates which can produce hyperreactivity, nitric acid tended to produce hyporeactivity (Schlesinger et al. 1994, 1995).

Cancer

Considerable attention has been addressed to the possibility that nitric acid, like other strong inorganic acids, might contribute to the development of lung or laryngeal cancer in workers exposed to acid mists (IARC 1992). Those acids often occur in combination, and sulfuric acid has been considered the compound most likely to be responsible for any such effect, but they could share a mechanism of toxic action. Soskolne et al. (1989) reviewed the existing information to evaluate whether acids are likely to cause chronic effects, particularly cancer. They focused on the sulfuric acid literature, but asserted that the chronic tissue irritation associated with acid exposure and the perturbations of cellular functioning arising from pH extremes are plausible mechanisms of genotoxic and carcinogenic activity. Swenberg and Beauchamp (1997) concurred that a carcinogenic mechanism of action was feasible but concluded that the evidence from experimental animals neither strongly supports nor refutes the induction of cancer by inorganic acid mists.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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Only the experiments of Ballou et al. (1978, 1981) included nitric acid as a test agent; it was used in parallel with hydrochloric acid and sulfuric acid. No significant increases in neoplasia were observed when groups of male rats with short-term inhalation exposure (30 minutes or six 6-hour exposures over 2 weeks) to nitric acid or to other acids were observed over their lifetimes and then compared with untreated and water-vapor-exposed controls.

Genotoxicity

Nitric acid specifically has been subjected to minimal genotoxicity testing that might illuminate any role in respiratory carcinogenesis. ToxNet’s Gene-Tox database lists only a virally enhanced cell-transformation assay in Syrian hamster ovary cells with negative results (Heidelberger et al. 1983).

In reviewing nonphysiologic culture conditions that might contribute to positive results of in vitro genotoxicity assays, Scott et al. (1991) concluded that acid pH (but not specifically nitric acid) can produce chromosomal aberrations in a variety of in vitro test systems. Swenberg and Beauchamp (1997) noted that low pH can enhance the occurrence of DNA modifications (by depurination or deamination) that might lead to point mutations and might induce chromosomal aberrations. It is implausible, however, that occupational exposures would cause systemic alterations in pH.

Other Health Outcomes

Soskolne et al. (1989) hypothesized that chronic tissue irritation and extremes of pH associated with acid exposure might foster developmental insults and increase susceptibility to infection. IARC’s review of strong inorganic acid mists (1992), however, found no toxicology studies addressing nitric acid’s potential to generate reproductive or developmental effects, nor did the present committee’s literature search reveal any reproductive-toxicity or immunotoxicity studies.

Genetic Susceptibility

No studies were found that addressed variability in susceptibility to the toxic effects of nitric acid, either between species or among individuals of a given species.

Interactions

The fact that RFNA with a higher concentration of nitrogen dioxide than WFNA (8–17% vs 0.1–0.4%) was found to have a lower LC50 (310 ppm vs 334 ppm) (Gray et al. 1954b) has been interpreted as suggesting that nitric acid has a synergistic effect on the primary irritating effect of nitrogen dioxide. Conversely, Mautz et al. (1988) hypothesized that the observed synergy of ozone and nitrogen dioxide is due to their reaction in situ to form nitric acid.

Rats and rabbits have been exposed to various combinations of nitric acid, ozone, and particles intended to simulate actual mixtures of ambient air pollution in California (as opposed to the sulfuric acid combinations that would be representative of air pollution in the eastern United States). Cells recovered from those animals by bronchiolar lavage were used in a variety of bioassays. The findings from chamber studies suggest that nitric acid does contribute to producing features similar to those of human bronchitis and emphysema (Keinman et al. 1995; Mautz et al. 1995; Schlesinger et al. 1995). Beyond the irritating effects of the H+ ion shared with other acids, the nitrate anion itself may have some toxic activity (Schlesinger et al. 1994). Nitric acid appears to be at most mildly synergistic with ozone and particles. The persistence of this set of respiratory effects has not been established.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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EPIDEMIOLOGIC STUDIES

The relationship between occupational exposure to chemicals that may have been released from disintegrating Scud missiles (possibly UDMH and RFNA) and the development of long-term, adverse health effects has been examined in several retrospective cohort, case-control, and cross-sectional studies of the general public. Several studies of Gulf War veterans, most of which were cross-sectional and conducted years after the war, did inquire about exposure to scud missile debris. The studies of Gulf War veterans pertaining to possible Scud-related exposures are described below. Similar discussions of occupational studies concerning exposure to hydrazines or to nitric acid and other strong inorganic acids follow with summaries of their most relevant findings.

Gulf War Veteran Studies and Scud Missile Debris Exposure

All the studies of Gulf War veterans and exposure to Scud missile debris reviewed by the committee used questionnaires to identify a broad array of biologic and chemical exposures (usually 10–20 per study) and symptoms (often 25–100 in a checklist format) experienced by the veterans, but few involved any confirmation with clinical examinations or laboratory tests. This sort of study design—involving a host of self-reported symptoms and exposures—has limitations for drawing inferences about symptom-exposure relationships.

About 43% of veterans in the largest, most representative population-based study of US veterans reported exposure to Scud missile debris (Kang et al. 2000), so such exposure during the war was perceived to be common although the Department of Defense (DOD 2001) reported that there were fewer than 50 instances of Scud disintegration that might have exposed US troops.

Several major Gulf War health studies included Scud debris in their lists of exposure options. Some provide evidence of a relationship between self-reported Scud debris exposure and a self-reported health effects; others do not. The studies’ key findings with respect to Scud missile debris exposure are summarized below.

Cohorts of Gulf War veterans from Ft. Devens, MA, and New Orleans, LA, have been followed longitudinally and reported on in a series of articles. Surveys were carried out shortly after return in 1991 and at 2-year intervals thereafter: 1992–1993, 1994–1995, and 1996–1997. The survey conducted in 1994–1995 (Proctor et al. 1998) was the first of these to examine symptom-exposure relationships. The study’s nearly 300 subjects represented a stratified random sample of 2,949 troops from Ft. Devens and 928 troops from New Orleans, both consisting of active-duty, reserve, and National Guard troops deployed to the Gulf. The response rates for Ft. Devens and New Orleans were 85% and 58%, respectively, of subjects from an earlier study who could be found and contacted again. The control group consisted of 50 veterans deployed to Germany during the Gulf War era (December 1990–August 1991).

Proctor et al. (1998) analyzed the relationships between the subjects’ responses to an eight-item exposure questionnaire and a checklist of symptoms experienced during the previous 30 days, adjusted for an index of combat stressors and posttraumatic stress disorder (PTSD) status as determined in a diagnostic interview. Each of the 52 symptoms on the symptom checklist was assigned to one of nine body systems (such as muscoskeletal symptoms) by four independent judges (an occupational-health physician, an environmental-health specialist, an environmental epidemiologist, and a neuropsychologist). Multiple regression adjusted for age,

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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sex, education, combat stress score, and PTSD diagnosis found that “debris from Scuds” was associated with musculoskeletal (p=0.017),1 neurologic (p<0.001),2 neuropsychologic (p=0.001),3 and psychologic4 symptoms (p=0.001). White et al. (2001) reported on more detailed assessment of neuropsychologic functioning obtained with a neurobehavioral test battery on the same cohort and found no relationship between exposure to Scud debris and poorer performance.

Unwin et al. (1999) mailed questionnaires to population-based random samples of UK veterans deployed to the Gulf War, deployed to Bosnia, or serving but not deployed during the Gulf War era. The self-reported symptoms (within the previous 30 days) and military experiences (including having been within 1 mile of a Scud missile explosion) were contrasted among these groups of respondents. For three clusters of health outcomes of interest—Centers for Disease Control and Prevention (CDC) multi-symptom syndrome, posttraumatic stress reaction, and poor physical functioning—Scud missile debris exposure was uniformly more frequently reported by veterans with each of the sets of symptoms. The estimated Scud missile debris-related risk was higher for those deployed to Bosnia, but for all three symptom clusters the increase was greater than unity only for the Gulf War veterans; numerous other exposures, however, were found to be considerably more strongly associated with these health outcomes.

Reid et al. (2001) studied subgroups of British veterans meeting criteria for chronic fatigue syndrome (CFS)5 or for multiple chemical sensitivity (MCS) among the respondents to the earlier investigation (Unwin et al. 1999). MCS was increased in the Gulf War sample (frequency 1.3%, 95% CI 1.0–1.7) in comparison with both the Bosnia-deployed (frequency 0.3%, 95% CI 0.1–0.6) and the era veterans (frequency 0.2%, 95% CI 0.1–0.4), whereas the frequency of CFS among the Gulf War veterans (2.1%, 95% CI 1.6–2.6) was increased only in comparison with the veterans deployed to Bosnia (0.7%, 95% CI 0.4–1.2). There was an association between Scud missile debris exposure and CFS in the 76 Gulf War veterans with CFS (OR 2.6, 95% CI 1.5–4.6). The 46 Gulf War veterans with MCS (who included seven of the CFS cases) were not more likely to report Scud debris exposure than the other Gulf War veterans (OR 1.6, 95% CI 0.8–3.0).

Goss Gilroy Inc. (1998) received 6,552 mailed responses from a cohort of almost 10,000 consisting of all Canadian Gulf War veterans and a similar sample of concurrent Canadian forces serving elsewhere. Exposure to Scud missile debris (exploding within 1 km) was one of about 10 exposures lumped into a broader category, created by the authors, termed “psychologic stressors”. Other exposures in this category included dead animals; handling prisoners of war (POWs); wearing protective gear other than for training; hearing chemical alarms sounding; having artillery, rockets, mortars, or anything else other than Scud missiles explode in the air 1 km away; witnessing anyone dying; and handling dead bodies. The authors found many relationships between various symptoms and exposure to this category of “psychologic stressors”, but the category is so heterogeneous that it would have been difficult to tie any health effect directly to Scud missile debris exposure.

The Danish Gulf War Study secured health information on 686 of the 821 peacekeeping forces sent to the Gulf from August 1990 through 1997 and contrasted it with that on 231

1  

Joint pains, backaches, and neckaches or stiffness.

2  

Headaches, numbness in arms or legs, and dizziness.

3  

Difficulties in learning new material, difficulty in concentrating, and confusion.

4  

Inability to fall asleep, frequent periods of feeling depressed, and frequent periods of anxiety or nervousness.

5  

A “case” of CFS was defined using veterans’ responses to the study’s fatigue scale and the Short Form-36 measure of functional disability. This combination was chosen to approximate the CDC criteria for CFS (Fukuda et al. 1994).

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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nondeployed military controls (Ishoy et al. 1999b, 2001b). Having been within 2 km of a Scud missile explosion was one of 26 physical, chemical, or biologic exposures investigated for possible association with particular adverse health outcomes. No relationship was found between Scud debris exposure and neuropsychologic symptom clusters (Suadicani et al. 1999), gastrointestinal symptoms (Ishoy et al. 1999a), or male sexual problems (Ishoy et al. 2001a).

Spencer et al. (2001) conducted a nested case-control study of exposure-symptom relationships in cases of unexplained illness (UI) (n=241) and healthy controls (n=113) drawn from among 1,119 responders in an earlier mailed survey of Gulf War veterans in Oregon and Washington (Spencer et al. 1998). Investigators used a new case definition for UI (Storzbach et al. 2000) in addition to the more restrictive CDC definition, according to which 115 subjects met the criteria of UI. On the basis of test-retest reliability and other factors, the 144 items on the original exposure questionnaire were winnowed down to 44. Two types of Scud missile debris exposures were among the 44 items retained: “heard Scud alarms” one to five times, six to 30 times, or more than 30 times; and “saw Scud detonate one to five times, six to 30 times, or more than 30 times. Those showed no association with either case definition of UI, whereas a more indirect index of Scud effects (inadequate protection during chemical/Scud alarms) was associated with both case definitions of UI but somewhat more strongly with the CDC definition (OR 3.16, 95% CI 1.28–7.80) than with the more inclusive one (OR 2.39, 95% CI 1.03–5.56). None of those factors was carried into the multivariate logistic modeling analysis.

Fiedler et al. (2000) studied veterans drawn from the DOD registry, comparing 58 subjects who met the case definition of CFS (35 with and 23 without psychiatric comorbidity) with 45 healthy controls. A set of Gulf War exposures (including “Scud debris”) derived from the questionnaire developed for the Ft. Devens cohort was used again in this study. As for all the exposure options, more Gulf War veterans with CFS (with or without psychiatric problems) reported environmental exposures, including Scud debris exposure, than did the healthy control veterans (p<0.0001). Unlike most of the other exposure options, Scud debris was not reported to have made the CFS subjects ill at the time of exposure more frequently than the controls.

Using factor analysis on the symptoms reported by 10,423 US Gulf War veterans and 8,960 of their nondeployed contemporaries who responded to a mailed survey (Kang et al. 2000), Kang et al. (2002) identified a new neurologic syndrome associated with Gulf War service characterized by four symptoms: loss of balance or dizziness, speech difficulty, sudden loss of strength, and tremors or shaking. The 277 Gulf War veterans who had all four of those symptoms were categorized as having the syndrome; 6,730 Gulf War veterans who had none of the symptoms were retained as controls. Having been within a mile of a Scud missile explosion was not among the nine exposures that were at least 3 times more commonly reported by the cases than by the controls.

Thus, the results from Gulf War veteran studies regarding Scud missile debris exposure and health effects is mixed, with no consistent pattern emerging.

Occupational Studies of Hydrazine Exposure

The designs, strengths, and weaknesses of the various epidemiology studies related to possible long-terms effects of exposure to hydrazine are summarized in Table 9.3.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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Cohort Studies
US Aerospace Cohort

Ritz et al. (1999) conducted a retrospective cohort study of aerospace workers involved in testing the performance of rocket engines using hydrazines (hydrazine, MMH, and UDMH) or other fuels (such as kerosene, liquid oxygen, and beryllium). Because radiation-related activities were also conducted at the facility, those who had ever been monitored for radiation were excluded, leaving 6,107 male subjects employed at the plant for at least 2 years from 1950 to 1980. Death certificates for 1,391 subjects who died in 1960–1994 were obtained from plant pension files or from state vital-statistics offices. Underlying cause of death was abstracted and coded according to ICD-9 by a licensed nosologist. A job-exposure matrix was based on job titles and codes, facility records, manager reports, and an industrial-hygiene review. Monitoring data were not available, but there were inventories of the amount of hydrazines brought into the facility in 1955–1994. Because exposures typically resulted from accidents or unpredictable events, workers were put into presumptive-exposure groups on the basis of their jobs—high, medium, low, and unexposed—reflecting relative likelihood (rather than intensity) of having been exposed to hydrazine. Each person was placed in the highest exposure category in which he had worked for at least 6 months; a second categorization was based on the more stringent criterion of exposure for at least 24 months. In addition, logistic analyses were performed on each of the categorizations to allow for a 0-, 10-, or 15-year lag.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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TABLE 9.3 Epidemiologic Studies Related to Exposure to Hydrazines

Reference

Population (Study and Control Group)

Study Design

Health Outcomes Assessed

Agent and Exposure Assessment

Analysis and Adjustment

Comments

US Aerospace Cohort

Ritz et al. 1999

6,107 male workers employed at least 2 years in 1950–1980 at California rocket-engine testing facility

Retrospective cohort, mortality

Mortality 1960–1994: cancer deaths: lung (ICD-9 162), hematopoietic or lymphopoietic (ICD-9 200–208), bladder or kidney (ICD-9 188, 189), oral cavity-pharynx-larynx-esophagus (ICD-9 140–150, 161), pancreas (ICD-9 157); smoking-related cancers (except lung cancer) (ICD-9 140–150, 157, 161, 188, 189)

Hydrazine exposure assessed with job-exposure matrix generated from company records, extensive industrial-hygiene review of facility, and amount of hydrazines used yearly

Internal comparison with about 4,500 nonexposed subjects: conditional logistic regression adjusting for age, pay type, time since hire, or transfer to testing division

Long followup period (average, 29 years) but relatively small number of cancer deaths (404)

Smoking histories not available for all subjects, but analysis for “other” smoking-related deaths negative; for 295 subjects with smoking histories, smoking status not related to hydrazine-exposure group

Possible confounding exposures: kerosene fuels, chlorine, fluorine, nitric acid, trichloroethylene

Emphysema deaths (ICD-9 492)

Morgenstern and Ritz 2001

Same dataset as Ritz et al. (1999) considered with two other cohorts

 

 

 

Analyses of Ritz et al. (1999) plus external comparison with US white male population

Entire cohort used in external comparisons so dominated by nonexposed and healthy-worker effect that association with hydrazine exposure not evident

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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Reference

Population (Study and Control Group)

Study Design

Health Outcomes Assessed

Agent and Exposure Assessment

Analysis and Adjustment

Comments

UK Hydrazine-Production Cohort

Wald et al. 1984

427 men who worked at least 6 months in 1945–1971 at UK hydrazine plant

Retrospective cohort, mortality

Mortality through June 1982: cancers deaths: lung

High, moderate, or low exposure to hydrazine assessed from records of area of plant employment and expertise of factory manager

Only observed and expected numbers of deaths stratified by duration of exposure and years since first exposure

Subjects could contribute person-years at risk to multiple exposure categories, depending on which jobs were held; SMRs and confidence intervals can be calculated

21 (5%) could not be traced

Compared with men of England and Wales for same period (source not specified)

Morris et al. 1995

Followup of 406 men in cohort of Wald et al. (1984)

Retrospective cohort, mortality

Mortality through January 1992: cancer deaths: lung, digestive system IHD deaths

Same as for Wald et al. (1984)

SMRs presented stratified by both duration of exposure and years since first exposure

Cohort is quite small, but followup period is substantial

Percentage loss to followup not stated.

Confidence intervals can be calculated

Compared with men of England and Wales for same period (source not specified)

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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Reference

Population (Study and Control Group)

Study Design

Health Outcomes Assessed

Agent and Exposure Assessment

Analysis and Adjustment

Comments

Italian Power Plant Cohort

Cammarano et al. 1984

270 men employed at least 6 months in 1960–1969 at thermoelectric power plant in Italy

Retrospective cohort, mortality

Mortality through 1980; lung cancer deaths

Workers exposed to hydrazine solution during loading procedures

Expected values calculated from local cancer registry

Only 26 deaths, 15 of them from cancer

SMR and 95% CI can be calculated

Compared with death rates in Lombardy Cancer Registry.

Results stratified by <or≥ 10 years of exposure

Cross-Sectional Studies

King et al. 1969

140 missile-fuel handlers

Cross-sectional review of existing records

Review of reports of annual physicals (1966–1968), including liver, pulmonary, blood, and urine studies; liver biopsies of three subjects with abnormal findings

Known use of hydrazine as missile propellant, no quantification or sampling, considerable coexposure to other haptotoxins but no adjustment

Comparison with clinical standards

Sample of opportunity; no comparison group; no exposure quantification; and possible confounding toxic exposures

Petersen et al. 1970

350–400 people in Danish Air Force who worked with liquid rocket propellants

Cross-sectional

Of 1,193 workers, 46 men had increased SGPT; liver biopsies on 26 of these (six fatty, five uncertain, 15 normal)

UDMH among propellants used

Only biospied person’s possible UDMH exposure listed; no systematic analysis

Distribution of subjects with and without UDMH exposure among those with increased SGPT and entire sample not clear

Nomiyama et al. 1998

249 (140 exposed) male employees, 18–60 years old, from five Japanese plants manufacturing hydrazine hydrate

Cross-sectional

Clinical examinations; self-reported symptoms; review of insurance claims at three factories for prevalence of reported conditions

Hydrazine measured in air samples from work breathing zones and urine samples

Rate ratio for exposed vs nonexposed (operational sample size unclear)

Risk estimates expressed as rate ratios of 3-year prevalence from three of five plants for 1992–1994

Uniformity of insurance information questionable

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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For those with high exposure to hydrazine for a minimum of either 6 or 24 months, lung-cancer mortality was consistently increased irrespective of lag period. Adjusted rate ratios ranged from 1.68 (95% CI 1.12–2.52) for 6 months of exposure and no lag to 2.10 (95% CI 1.36–3.25) for 24 months of exposure with a latent period of at least 15 years. For both the 6-month and 24-month exposure classifications, the relative risks increased with increasing years of latency. For the medium exposure category, the estimates of lung-cancer risk were uniformly somewhat lower for all duration or lag-period combinations. In the analysis by decade of exposure (high exposure for at least 6 months), the highest risk was observed for the period 1960–1969 (RR 2.01, 95% CI 1.21–3.33), when the hydrazines were tested most intensively.

Ritz et al. (1999) invested considerable effort in investigating whether the result for lung-cancer mortality might be attributable to smoking rather than hydrazine exposure. For the 295 workers on whom some information about smoking history was available, no correlation was found between smoking and hydrazine exposure; hydrazine effects in this cohort are unlikely to have been confounded by smoking. Like lung cancer and bladder or kidney cancer, cancers of the upper aerodigestive tract (oral cavity, pharynx, larynx, and esophagus) and of the pancreas are considered to be smoking-related. For those cancer sites, however, risks were not increased by high hydrazine exposure for either more than 6 or 24 months; increases were seen in the medium exposure groups (6 months of exposure: RR 1.69, 95% CI 0.47–6.06; 24 months of exposure: RR 1.18, 95% CI 0.26–5.27). For all the smoking-related cancers (other than lung) combined or for emphysema deaths, the risk estimates followed a similar pattern. The lack of increased risk for any of those cancers with high exposure to hydrazine supports the idea that the positive lung-cancer finding was not due to confounding with smoking.

Mortality from hematopoietic or lymphopoietic cancers increased in both medium and high exposure groups, regardless of duration; risk increased slightly, but consistently with lag. With the full 15 years of lag, however, instead of increased risk with duration of exposure, the only increase was for high exposure of at least 6 months (RR 2.83, 95% CI 1.22–6.56). For those cancers, the risk was most markedly increased for the decade 1960–1969 (RR 2.45, 95% CI 0.91–6.58).

Relative risks were also increased for death from bladder or kidney cancer among those with high exposure to hydrazine for at least 6 months (RR 1.65, 95% CI 0.59–4.56) or 24 months (RR 1.80, 95% CI 0.63–5.12) and 15-year lag. No deaths from bladder or kidney cancer were reported among subjects with medium exposure. Mortality, however, is not the best measure of incidence of a cancer that is not highly fatal, as bladder cancer is.

Overall, the investigation was well conducted; it had relatively large numbers of exposed cases, derived exposure duration and latency information on an individual basis, and used a job-exposure matrix to determine probability of exposure to hydrazine. Morgenstern and Ritz (2001) reanalyzed the cohort in this study in comparison with the general US population (in parallel to two other cohorts from the same facility that had potential radiation exposure) and had results virtually identical with those reported here.

UK Hydrazine Production Cohort

A retrospective cohort of 427 male workers at a hydrazine plant in the UK consisted of those who had been employed for at least 6 months in 1945–1971. This population was 95% traceable at the time of the initial followup through 1982 (Wald et al. 1984). Morris et al. (1995) continued the mortality followup of the traceable 406 men through 1992 (an average of 30 years). Exposure to hydrazine was assessed by using the expertise of the factory manager and records indicating where in the plant each subject had been employed. Although no

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
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measurements of atmospheric hydrazine had been made, the researchers believed ambient concentrations in the hydrazine-production area of the plant had been 1–10 ppm and near the storage vessels as high as 100 ppm. On the basis of jobs held, each subject was allocated to the groups for which results were presented—high exposure (directly involved in hydrazine production for at least 6 months) or low to moderate exposure. Data on mortality were gathered from the National Health Service records for each employee. Observed incidences were determined by 5-year age groups and compared with expected values derived from men in England and Wales in the same age groups during the same period. Results were presented with and without the constraint of a 10-year latency since first exposure.

For most health outcomes over both followup intervals, the number of expected deaths exceeded the number of observed deaths in the exposed cohort; this implied a healthy-worker effect. The lung was the only cancer site for which observed deaths surpassed the number expected for those working in a high-exposure job for 6 months or more (3 observed vs 2.79 expected); the risk was slightly more increased for those with at least 10 years since first exposure (SMR 1.23, 95% CI 0.25–3.61).

In the low-to-moderate exposure category, cancers of the digestive system were somewhat increased (SMR 1.24, 95% CI 0.57–2.34); no cancers of this type were observed in the high-exposure group. The ICD codes included in this category were not specified, but it is improbable that they correspond to the “upper aerodigestive tract” sites considered by Ritz et al. (1999).

The distribution of ischemic-heart-disease (IHD) deaths suggests that the small increase observed in those who had held a high-exposure job for at least 2 years (SMR 1.08, 95% CI 0.47–2.13) merely represents a random perturbation.

The relatively small number of observed deaths limits the interpretation of the study results. Given that hydrazine exposure was based on jobs listed in employment records, subjects who switched jobs in the company and thus had varied levels of exposure may have diluted the effects of stratification presented by person-years. The methods and interval of followup appear adequate, although Morris et al. (1995) did not report whether more subjects had proved untraceable from 1982 to 1992 in addition to the 5% who were untraceable in the first study.

Italian Power Plant Cohort

Cammarano et al. (1984) conducted a cancer-mortality study among 270 male workers in a thermoelectric power plant in Turbigo (Milan, Italy). The men had worked in the plant for at least 6 months in 1960–1969. on the basis of company registers and census data, all subjects were followed up through 1980. For each of the 26 subjects found to have died during the study period, cause of death was ascertained from the registry of the municipality where the death occurred. Attempts were made to interview next of kin and to trace clinical records where information was lacking or of poor quality. The numbers of expected deaths for various causes were computed from the 1976–1977 Lombardy Cancer Registry for Varese Province, which is within 5 km of Turbig, the small town where most of the workers lived. Analysis of the processes used at the plant indicated that a number of toxic substances in addition to hydrazine were present in the work environment (polycyclic aromatic hydrocarbons (PAHs), asbestos, polychlorinated biphenyls (PCBs), chromium, nickel, and beryllium); the researchers made no assertions about which agent(s) might be responsible for any increase in risk.

The two observed lung-cancer deaths occurred among the workers with 10 years or more of exposure, giving an increased risk estimate with a wide confidence interval (SMR 1.42, 95% CI 0.17–5.12). For all types of cancer, mortality was increased in the entire cohort (SMR 1.98,

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

95% CI 1.11–3.26), but the excess risk (SMR 2.76) was confined to those with 10 years or more of exposure. Although the results indicate a two-fold to threefold excess risk of cancer overall, the small numbers for each cancer type prevent the identification of any increased risk for a specific site. Furthermore, the effects of exposure to hydrazine cannot be isolated from the effects of the combination of exposures experienced in this work setting, and this limits the study’s contribution to the body of evidence on hydrazine as a specific causative agent.

Cross-Sectional Studies

Toxicologic data available since the middle 1950s indicated that hydrazine and UDMH have potential for hepatotoxicity (ATSDR 1997; Choudhary and Hansen 1998; NRC 1996; Shook and Cowart 1957; Wells 1908), so industrial-hygiene programs have included monitoring of liver function in workers exposed to hydrazines, as is evidenced by the studies described below.

Missile-Propellant Handlers at Vandenberg Air Force Base, CA

King et al. (1969) reviewed the records of physical examinations routinely conducted from 1966 through 1968 on 140 asymptomatic people who handled missile fuels (including hydrazine). The liver-function screenings generated the most atypical examination results: 17 people (12%) had increased serum glutamic pyruvic transaminase (SGPT) activity or thymol turbidity, and fatty changes were seen in two of the liver biopsies drawn from the three people with the extreme findings. Little can be concluded from those findings, because reviewed medical records were a sample of opportunity without enhancement by a comparison group, assessment of hydrazine exposure, or adjustment for confounding exposures.

Rocket-Propellant Workers in Danish Air Force

During the early 1960s, routine blood and urine analyses had been performed three or four times a year on 1,193 members of the Danish Air Force, including 350–400 involved in handling liquid rocket propellants (UDMH in particular). In the entire group, 46 men (4%) had one or more instances of increased SGPT; the prevalence of increased SGPT specifically among the propellant workers was not stated. Liver biopsies were performed on the 26 for whom there was not a ready explanation of the SGPT increase and who agreed to the procedure (Petersen et al. 1970). For each of the 26 people, a synopsis of possible exposure to UDMH was given. Six instances of fatty degeneration were found (all in people whose SGPT remained increased at the time of the biopsy) and five additional people had some suggestion of liver damage. All the biopsied subjects appeared to have had some opportunity for UDMH exposure, so an association with liver damage was not obvious in this set. There was no systematic analysis of the relationship between UDMH exposure, SGPT readings, and biopsy findings for the entire sample, so the biopsied subjects constitute a set of case histories. Petersen et al. (1970) expressed interest in whether the hepatic effects would persist after exposure to UDMH ceased, but no report of such a followup study was found.

Japanese Hydrazine Hydrate Workers

Nomiyama et al. (1998) studied workers at five factories in Japan that made hydrazine hydrate (HH) or hydrazine derivatives. After exclusion of 48 subjects who had hepatitis B/C antigens or diabetes, the analysis consisted of 249 males 18–60 years old, of whom 140 had been exposed to hydrazines for 0.5–34 years. A combination of personal air sampling and biologic monitoring (urinary excretion of hydrazine and acetylhydrazine) demonstrated no exposure of the control subjects and an average of 11 ppb in the breathing zones of HH workers. Subjects

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

were given clinical examinations, and they completed questionnaires regarding subjective symptoms, smoking and alcohol and caffeine consumption, and past and present medical history, including exposure to chemical products and medications. Insurance-claim records from 1992 through 1994 from three of the five factories were used to determine prevalence rates of disease. Self-reported symptoms and clinical findings did not differ systematically with exposure. The insurance claims suggested increased risks among HH-exposed workers for viral hepatitis (RR 1.99, 95% CI 1.15–3.43), cirrhosis (RR 2.48, 95% CI 1.51–4.08), thyroid disorders (RR 2.48, 95% CI 1.51–4.08), and cerebrovascular disease other than cerebral infarction (RR 2.26, 95% CI 1.35–3.78). The exposure assessment in this study was well performed. The validity of insurance claims as a proxy for diagnosed diseases, however, limits the interpretation of the findings, because diagnostic criteria would not be expected to be uniform. Presumably, exposure continued during the 3-year period when insurance claims were submitted, so the issue of persistence was not addressed.

Summary

Overall, relatively few epidemiologic studies of exposure to UDMH specifically or hydrazines in general are available. Only a single specific health outcome—lung cancer—was represented in all three cohort mortality studies reviewed by the committee (Cammarano et al. 1984; Morris et al. 1995; Ritz et al. 1999), and they all suggested the possibility of an increase in risk. The analysis of the US cohort by Ritz et al. (1999) demonstrated an association between hydrazine exposure, based on a job-exposure matrix, and risk of lung cancer. Several sources of potential confounding, including sex and radiation exposure, were controlled by study design. Other potentially confounding variables were controlled in multivariate analysis, including age, pay type (a proxy for socioeconomic status), and time since hire or transfer (a proxy for the selective loss of less healthy workers). Although smoking status of most workers was unknown, there was indirect evidence that smoking did not confound the results. There was no association between hydrazine-exposure category and smoking status in a subset of workers who completed a health survey. Moreover, there was no relation between hydrazine-exposure category and the risk of smoking-related nonrespiratory cancers and emphysema. The committee conducted a sensitivity analysis that factored in uncertainties about smoking frequencies in the exposed and nonexposed workers, which gave further assurance that full knowledge of and adjustment for smoking would be unlikely to broaden the reported confidence intervals for lung cancer to include 1.0.

The other two retrospective cohort studies (Cammarano et al. 1984; Morris et al. 1995) of lung cancer were limited by small sample and inadequate study power. In addition, the study of Italian power-plant workers (Cammarano et al. 1984) was limited by its failure to control for coexposure to other carcinogenic substances, including asbestos and PAHs. The lack of internal control subjects and the lack of information on smoking constitute major limitations for both studies. That the confidence interval for lung cancer after high likelihood of exposure to hydrazines as compared with nonexposed internal controls found by Ritz et al. (1999) lies above 1.0 and completely within that of the negative finding in comparison with external control rates (Cammarano et al. 1984) indicates no inconsistency. Consequently, there is inadequate evidence to evaluate the consistency of the association between hydrazine and lung cancer beyond the strong study by Ritz et al. (1999).

Results of experimental studies involving oral and inhalation exposures to hydrazine, UDMH, and MMH show an increased incidence of various types of tumors in animals.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Malignant and benign tumors and preneoplastic changes, have been identified at several sites—including the lung, liver, and nose—in mice, rats, and hamsters exposed to hydrazines; and the available data support a dose-related occurrence of those lesions (Biancifiori 1970; Biancifiori et al. 1964, 1966; Bosan et al. 1987; Kinkead et al. 1985; Mommsen et al. 1982; Roe et al. 1967; Severi and Biancifiori 1968; Steinhoff and Mohr 1988; Toth 1969; Vernot et al. 1985). In vivo and in vitro studies on hydrazines have demonstrated potential mechanisms of carcinogenicity, including mutagenesis, DNA alkylation, and tissue injury (ATSDR 1997). Those mechanisms may be relevant to the carcinogenicity of hydrazines in humans.

The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between exposure to hydrazines and lung cancer.

The three cohorts reviewed reported somewhat increased mortality from cancer at sites other than the lung (hematopoietic and lymphopoietic, bladder and kidney, digestive tract, and pancreas) and from two noncancer conditions (emphysema and ischemic heart disease). The possibility of nonspecific hepatic effects was raised by three cross-sectional reports, but the studies were largely opportunistic compilations of available information that did not adhere to explicit protocols. The available epidemiologic studies do not provide adequate or consistent evidence of an association between exposure to hydrazines and any of those health outcomes.

The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to hydrazines and hematopoietic or lymphopoietic cancers, bladder or kidney cancer, digestive tract cancer, pancreatic cancer, mortality from emphysema or ischemic heart disease, or hepatic effects.

Table 9.4 provides the key findings that the committee evaluated in drawing its conclusions of association for exposure to hydrazine.

Occupational Studies of Nitric Acid Exposure

The designs, strengths, and weaknesses of the various epidemiology studies related to possible long-terms effects of exposure to nitric acid are summarized in Table 9.5.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

TABLE 9.4 Selected Epidemiologic Studies—Health Outcomes and Exposure to Hydrazines

Reference

Study Population

Exposed Cases

Estimated Relative Risk Lung Cancer

Cohort Studies

Ritz et al. 1999

Male US rocket-engine workers

 

 

 

Nonexposed

1.0

 

Nonexposed or low exposure, ≥6 months (from Morgenstern and Ritz et al. 2001)

97

 

Medium exposure, ≥6 months

 

 

No lag

5

0.41 (0.17–1.02)

10-year lag

4

0.36 (0.13–0.98)

15-year lag

4

0.42 (0.15–1.16)

High exposure, ≥6 months

 

 

No lag

44

1.68 (1.12–2.52)

10-year lag

42

1.70 (1.13–2.56)

15-year lag

41

1.93 (1.27–2.93)

Medium exposure, ≥24 months

 

 

No lag

7

0.66 (0.31–1.44)

10-year lag

6

0.65 (0.28–1.49)

15-year lag

5

0.65 (0.26–1.62)

High exposure, ≥24 months

 

 

No lag

36

1.70 (1.11–2.59)

10-year lag

34

1.76 (1.15–2.71)

15-year lag

34

2.10 (1.36–3.25)

Decade of Exposure (high exposure, ≥6 months)

 

 

1950–1959

NA

0.88 (0.54–1.44)

1960–1969

NA

2.01 (1.21–3.33)

1970–1979

NA

1.45 (0.70–3.01)

1980–1989

NA

0.46 (0.06–3.64)

Morris et al. 1995

Male UK hydrazine-plant workers

 

 

 

Any exposure (≥6 months at plant)

8

0.66 (0.29–1.31)a

≥10 years since first exposure

8

0.74 (0.32–1.46)a

Moderate/low exposure

5

0.54 (0.17–1.26)a

≥10 years since first exposure

5

0.60 (0.19–1.40)a

High exposure

 

 

>6 months duration

3

1.08 (0.22–3.14)a

≥10 years since first exposure

3

1.23 (0.25–3.61)a

≥2 years duration

1

0.41 (0.01–2.30)a

≥10 years since first exposure

1

0.47 (0.01–2.64)a

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk

Cammarano et al. 1984

Italian power-plant workers

 

 

 

All subjects

2

0.87 (0.11–3.15)b

<10 years exposure

0

0

≥10 years exposure

2

1.42 (0.17–5.12)b

Bladder/Kidney Cancer

Cohort Study

Ritz et al. 1999

Male US rocket-engine workers

 

 

 

Nonexposed

 

1.0

Medium exposure, ≥6 months, 15-year lag

0

High exposure, ≥6 months, 15-year lag

7

1.65 (0.59–4.56)

Medium exposure, ≥24 months, 15-year lag

0

High exposure, ≥24 months, 15-year lag

6

1.80 (0.63–5.12)

Lymphopoietic Cancer

Cohort Study

Ritz et al. 1999

Male US rocket-engine workers

 

 

 

Nonexposed

 

1.0

Nonexposed or low exposure, ≥6 months (from Morgenstern and Ritz et al. 2001)

35

 

Medium exposure, ≥6 months, 15-year lag

5

1.79 (0.65–4.94)

High exposure, ≥6 months, 15-year lag

11

2.83 (1.22–6.56)

Medium exposure, ≥24 months, 15-year lag

4

1.32 (0.45–3.90)

High exposure, ≥24 months, 15-year lag

6

1.42 (0.54–3.72)

Decade of exposure (high exposure, ≥6 months)

 

 

1950–1959

NA

0.86 (0.32–2.28)

1960–1969

NA

2.45 (0.91–6.58)

1970–1979

NA

0 (0--)c

1980–1989

NA

0.89 (0--)c

Oral Cavity, Pharyngeal, Laryngeal, or Esophageal Cancers (“Upper Aerodigestive Tract Cancers”)

Cohort Study

Ritz et al. 1999

Male US rocket-engine workers

 

 

 

Medium exposure, ≥6 months, 15-year lag

3

1.69 (0.47–6.06)

High exposure, ≥6 months, 15-year lag

3

0.69 (0.19–2.53)

Medium exposure, ≥24 months, 15-year lag

2

1.18 (0.26–5.27)

High exposure, ≥24 months, 15-year lag

2

0.57 (0.13–2.61)

Digestive Tract Cancer

Cohort Study

Morris et al. 1995

Male UK hydrazine-plant workers

 

 

 

Any exposure (≥6 months at plant)

9

0.95 (0.44–1.81)a

≥10 years since first exposure

8

0.95 (0.41–1.87)a

Moderate/low exposure

9

1.24 (0.57–2.34)a

≥10 years since first exposure

8

1.22 (0.53–2.41)a

High exposure

0

0.0

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk Pancreatic Cancer

Cohort Study

Ritz et al. 1999

Male US rocket-engine workers

 

 

 

Nonexposed

 

1.0

Medium exposure, ≥6 months, 15-year lag

4

1.95 (0.62–6.12)

High exposure, ≥6 months, 15-year lag

2

0.48 (0.10–2.25)

Medium exposure, ≥24 months, 15-year lag

4

2.26 (0.72–7.09)

High exposure, ≥24 months, 15-year lag

1

0.32 (0.04–2.51)

Smoking-Related Cancers (other than lung; ICD-9 140–150, 157, 161, 188, 189) (presented as evidence that smoking is not confounder)

Cohort Study

Ritz et al. 1999

Male US rocket-engine workers

 

 

 

Nonexposed

 

1.0

Medium exposure, ≥6 months, 15-year lag

7

1.22 (0.54–2.76)

High exposure, ≥6 months, 15-year lag

12

0.94 (0.47–1.86)

Medium exposure, ≥24 months, 15-year lag

6

1.17 (0.49–2.79)

High exposure, ≥24 months, 15-year lag

9

0.90 (0.42–1.92)

Emphysema Deaths (presented as evidence that smoking is not confounder)

Cohort Study

Ritz et al. 1999

Male US rocket-engine workers

 

 

 

Nonexposed

 

1.0

Medium exposure, ≥6 months, 15-year lag

4

2.18 (0.72–6.62)

High exposure, ≥6 months, 15-year lag

3

0.54 (0.15–1.93)

Medium exposure, ≥24 months, 15-year lag

3

2.26 (0.64–8.02)

High exposure, ≥24 months, 15-year lag

3

0.74 (0.21–2.65)

Ischemic Heart Disease

Cohort Studies

Morris et al. 1995

Male UK hydrazine-plant workers

 

 

 

Any exposure (≥6 months at plant)

26

0.70 (0.46–1.03)a

≥10 years since first exposure

23

0.69 (0.44–1.03)a

Moderate/low exposure

18

0.63 (0.37–1.00)a

≥10 years since first exposure

16

0.62 (0.35–1.01)a

High exposure

 

 

≥6 months duration

8

0.94 (0.40–1.85)a

≥10 years since first exposure

7

0.92 (0.37–1.90)a

≥2 years duration

8

1.08 (0.47–2.13)a

≥10 years since first exposure

7

1.06 (0.43–2.18)a

NOTE: na=not available.

a95% CIs calculated with standard methods from observed and expected numbers presented in original paper.

bRisk estimate and 95% CI calculated with standard methods from observed and expected numbers presented in original paper.

cUpper limits could not be estimated because of the small numbers of outcome events in the high-exposure category.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

TABLE 9.5 Epidemiologic Studies Related to Exposure to Nitric Acid

Reference

Study Populations

Study Design

Health Outcomes Assessed

Agent and Exposure Assessment

Analysis and Adjustment

Comments

Pennsylvania Sheet and Tin Mill Cohort

Mazumdar et al. 1975

8,465 white male sheet and tin mill workers among 58,828 male steel workers employed in 1953 at seven Allegheny County, Pennsylvania, plants

Prospective cohort mortality

Mortality through 1966 assessed from death certificates:

cancer:

respiratory, lymphatic/hemat opoietic,

various heart diseases (if employed ≥5 yr before 1954)

Fumes from acid baths related to work in pickling, coating, or specialty finishing processes

RR calculated from observed deaths in each work area against expected deaths from remainder of total cohort

Small numbers observed and expected preclude calculation of stable CIs for many combinations of jobs and health outcome;

ICDs not given

Swedish Metal Pickling Cohort

Ahlborg et al. 1981

110 men employed at least 1 year at pickling house in 1951–1979

Retrospective cohort

Mortality through 1979:

cancer:

respiratory tract, laryngeal

Nitric acid component of pickling baths

Expected numbers calculated by sex, calendar year, and age from Swedish Cancer Registry for 1958–1979

This was basically a note reporting a cluster of three laryngeal cancers; smoking not accounted for

US Midwestern Metal Pickling Cohort

Beaumont et al. 1987

1,165 workers employed at least 6 months in 1940–1965 at one of three midwestern steel-manufacturing facilities in pickling-related job, followed through 1981

Retrospective cohort mortality

Mortality through Oct. 27, 1981:

diabetes focus on lung cancer

Nitric acid one of “other acids” used in pickling operations

SMRs for all vs US population; white males working 1950–1954 vs Allegheny County steel workers to control for smoking and other socioeconomic factors

Lung-cancer excess stronger among those exposed to acids other than sulfuric than for those exposed to sulfuric acid only; several approaches taken to show increase not due solely to smoking

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Populations

Study Design

Health Outcomes Assessed

Agent and Exposure Assessment

Analysis and Adjustment

Comments

Steenland et al. 1988

Subset of 879 subjects from Beaumont et al. (1987) for whom determinations of ever having had laryngeal cancer could be made

Retrospective cohort

Incidence of laryngeal cancer through early 1986 determined by interviews with living subjects or next of kin, plus medical record reviews; information on smoking also gathered

Nitric acid among acids used in pickling operations

Expected figures calculated from US population data with adjustment for excess smoking in cohort

Significant increase in incidence of laryngeal cancer, but analyses not conducted in detail by three acid categories used in Beaumont et al. (1987)

Steenland and Beaumont 1989

1,156 males in cohort of Beaumont et al. (1987)

Retrospective cohort mortality

Mortality through early 1986:

lung cancer

Information on smoking gathered from subject or next of kin

Nitric acid component of acids used in pickling operations

SMRs calculated from US population from 1940–1978; adjustment for smoking by Axelson technique

Analysis was not stratified by types of acid exposure; control for smoking decreased risk of lung cancer just below significance

14% of those alive in 1981 (162) could not be traced

Italian Chemical Plant Workers

Rapiti et al. 1997

125 males ever exposed to acid mixtures among 505 workers at Italian chemical plant any time in 1954–1970

Retrospective cohort

Mortality 1970–1991 with focus on cancer

Scan of medical files containing work histories and annual examinations, as required by 1954 law; nitric and sulfuric acids used in some jobs

SMR (90% CIs) based on regional cause-specific death rates

Vital status determined for 96% of full cohort

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Populations

Study Design

Health Outcomes Assessed

Agent and Exposure Assessment

Analysis and Adjustment

Comments

Nitric Acid Production Cohort

Hilt et al. 1985

287 male production and maintenance workers first employed any time in 1928–1961 at nitric acid production plant and alive 1953, compared with national incidence data

Retrospective cohort

Histologically verified new cancer cases in 1953–1980 in Norwegian Cancer Registry; focus on lung cancers and pleural or peritoneal mesothelioma (plus cancers of unknown origin); also colon, stomach, melanoma

Asbestos exposure dominated exposure to nitric acid; excluded from consideration as key study

SIR with expectations calculated by 5-year age groups for 1953–1980 from Norwegian Cancer Registry; adjusted for smoking

Very significantly increased lung cancer in highly exposed and lightly exposed maintenance workers; nonsignificant O/E=1.6 (3 vs 1.9) for lightly exposed production workers (how many of 190 not stated) for whom nitric acid exposure might be perceptible factor

Hilt 1987

153 men working anytime in 1928–1970 at nitric acid production plant and “eligible” for clinical examination 1979–1980 followed through 1985

Prospective cohort

Lung fibrosis and/or pleural plaques, respiratory symptoms

Asbestos exposure dominated exposure to nitric acid; excluded from consideration as key study

Stratification by current, ex-, or never smoker

 

Hilt et al. 1991

287 subjects in Hilt et al. (1985) followed through 1988 (8 more years)

Retrospective cohort

Histologically verified new cancer cases in 1953–1988 in Norwegian Cancer Registry; focus on lung cancers and pleural or peritoneal mesothelioma (plus cancers of unknown origin); also colon, stomach, melanoma

Asbestos exposure dominated exposure to nitric acid; excluded from consideration as key study

SIR with expectations calculated by 5-year age groups for 1953–1988 from Norwegian Cancer Registry; adjusted for smoking

O/E for lung cancers among light-exposure group (not subdivided between maintenance and production workers) changed from 2.1 to 1.8 (5 vs 2.4 to 7 vs 4.0), both nonsignificant

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Populations

Study Design

Health Outcomes Assessed

Agent and Exposure Assessment

Analysis and Adjustment

Comments

Laryngeal Cancer Case-Control Studies

Soskolne et al. 1984

50 cases (34 laryngeal) of upper respiratory cancer diagnosed in 1944–1980 in employees of at least 1 year at chemical plant in Louisiana; 175 matched company controls

Case-control

“Upper respiratory” cancer

Work history records used to score occupations in ethanol units for level of exposure to sulfuric acid; occupations outside ethanol units unexposed

ORs; analysis adjusted for alcoholism, tobacco use, and history of ear, nose, or throat disease; controls matched on duration and first year of employment, age, sex, and race

 

Soskolne et al. 1992

183 men with histologically confirmed laryngeal cancer diagnosed in 1977–1979 in southern Ontario; 183 matched population controls

Case-control

Laryngeal cancer

Self-reported work histories coded by author for exposure to sulfuric acid

ORs; analysis adjusts for cigarette and alcohol use; controls matched on sex, age, and neighborhood

Zemla et al. 1987

328 male cases in Upper Silesia located through Institute of Oncology in Poland in 1980–1984; 656 controls without cancer matched on native or immigrant status

Case-control

Laryngeal cancer confirmed histopathologically

Self-reported history of occupational hazards including vapors containing sulfuric, hydrochloric, and nitric acid immigrants assumed to have shorter exposure to industrial pollution.

Unclear how “expected” figures obtained, necessary for chi2 tests and/or RRs

Nitric acid is assumed component of self-reported exposure; addressed confounding by smoking and alcohol consumption

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Populations

Study Design

Health Outcomes Assessed

Agent and Exposure Assessment

Analysis and Adjustment

Comments

Eisen et al. 1994

108 incident cases in cohort of automobile workers exposed to machining fluids at three Michigan plants ≥3 yrs before 1985; 540 cohort controls

Nested case-control

Laryngeal cancers detected through 1989

Acid mists (nitric, phosphoric, or sulfuric acid) used in restricted locations at two plants addressed as confounder to machining fluid exposure; exposure based on air sampling, historical records, and plant interviews

OR; used 10-year lags and adjusted for time since hire; controls matched for age, plant, race, and sex

Acid-mist years OR=0.90 (0.66–1.22)

Nitric acid included, but cannot separate its effect from that of other acids

De Stefani et al. 1998

112 incident and histologically confirmed cases from five hospitals in Montevideo from 1993–1995; 509 controls with cancers not related to tobacco or alcohol

Case-control

Laryngeal cancer

Self-reported exposure to strong acid (hydrochloric, nitric, and sulfuric) mists

ORs from unconditional logistic regression adjusted for age, residence, education, income, cigarette smoking, and alcohol consumption

Increased risk for ever exposed (1.6), 1–20 years (1.2), and 21+ years (1.8) of exposure;

Nitric acid was included, but cannot separate its effect from other acids

Gustavsson et al. 1998

157 cases of laryngeal cancer among Swedish-born men 40–79 years old living in Stockholm county or five southern counties (388 cases at other three cancer sites); 641 controls matched by region and age group drawn by stratified random sampling of population registers

Case-control

Sought all incident cases from Jan. 1, 1988 to Jan. 31, 1991 of squamous cell carcinoma of “upper gasointestinal tract” (oral cavity, pharynx, larynx, and esophagus reported individually; ICD-9 141, 143, 144, 146, 148, 150, 161); New cases reported weekly from local hospitals or regional cancer registries.

Questionnaire on lifestyle and work history administered by unblinded nurse; likelihood and intensity of 17 factors coded by occupational hygienist from work histories, including “acid mist”, PAHs

RRs by logistic regression adjusted for age, region, smoking, and alcohol use

Which acids included in “acid mist” category not specified

90% and 85% of identified 605 cases and 756 controls completed

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Populations

Study Design

Health Outcomes Assessed

Agent and Exposure Assessment

Analysis and Adjustment

Comments

Multiple Myeloma Case-Control Study

Morris et al. 1986

698 cases from four SEER registries from 1977–1981;

Case-control

Multiple myeloma

Toxicologist put interviews responses into 20 exposure groups; “acids” (included muriatic, hydrochloric, sulfuric, chromic, nitric, acetic, and other acids)

Mantel-Haenszel ORs adjusted for age, sex, race, and study site

Elevated risk (1.5; 0.8–2.8) for self-respondents, but no risk seen with addition of proxies;

1,683 population controls

Nitric acid was included, but cannot separate its effect from other acids

Bombay Nitric Acid Plant

Kamat et al. 1984

125 workers chronically exposed to nitric acid fumes

Cross-sectional

Respiratory symptoms (interview), lung function, radiography

Subjects’ exposure to nitric acid not estimated, but samples obtained at unidentified times and sites in the plant between 20–40 ppm

No analysis directly relates NO2 exposure to pulmonary function or radiographic abnormalities

Exposure assessment undefined

Indian Suburban Nitric Acid and Bombay Chemical Plants

Kolhatkar et al. 1987

113 male workers (70 in nitric acid plant and 43 in urban plant with exposure to nitric acid, plus other acids); 29 nonexposed male workers (15 and 14 from above plants)

Cross-sectional

Respiratory symptoms (interview), lung function, radiography

No measurement of nitric acid or liberated NO2 fumes; thought to exceed 2–15 ppm (“newer and cleaner” than nitric acid plant in Kamat et al. 1984); no explanation of means of allocation to exposed or nonexposed group

No analysis directly relates NO2 exposure to pulmonary function or radiographic abnormalities

Exposure assessment undefined

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×
Cohort Studies
Pennsylvania Sheet and Tin Mill Cohorts

Mazumdar et al. (1975) reported on the mortality experience through 1966 of a cohort of 8,465 white men who worked in the sheet and tin mills of seven plants in Allegheny County, Pennsylvania, in 1953 (a subset of a much larger NIOSH cohort of steelworkers). For 1,183 deceased subjects, a licensed nosologist coded underlying causes of death from death certificates according to ICD-7. Exposure to fumes from acid baths (said to contain sulfuric, hydrochloric, or phosphoric acid) was determined through a review of work-history records. Such exposures occurred in the pickling, coating, or specialty finishing processes, which were involved in six of 13 job classifications reported: batch pickling and sheet drying; continuous pickling and electric cleaning; stainless annealing, pickling, and processing; coating; sheet finishing and shipping; and tin finishing and shipping. The study did not specifically identify or evaluate exposure to nitric acid.

Relative risks were calculated from observed deaths in each work area and compared with the number of expected deaths from the remainder of the nonexposed cohort. Job-specific findings were presented for all cancers, with cancers of the respiratory organs or of lymphatic and hematopoietic tissues broken out separately. The incidence of all cancers was notably increased only in workers in stainless annealing, pickling, and processing (6 observed, 2.0 expected; RR 3.32, p<0.05); that one of these cases was a lymphohematopoietic cancer (0.2 expected) and two were respiratory (0.6 expected) suggests increases of both. Cancer of respiratory organs was modestly increased among those who had worked in coating (4 observed, 2.8 expected) or in sheet finishing and shipping (19 observed, 15.6 expected; RR 1.27).

Another cohort of men involved in metal pickling was studied by Ahlborg et al. (1981). One hundred and ten men were employed in a pickling house for at least 1 year in 1951–1979. Nitric acid is a known component of the pickling baths, but no attempts to quantify exposure were made. The incidence of cancers of the respiratory tract and larynx was compared with expected figures as calculated from sex, calendar year, and age for 1958–1979 in the Swedish Cancer Registry. Regardless of a 10-year induction period, there were four observed cases of respiratory tract cancer and three cases of laryngeal cancer. Those are notably higher than the expected figures of 0.66 (0.55 given a 10-year latency) and 0.06 (0.05 given a 10-year latency) respectively. Smoking habits of the subjects were not assessed or accounted for and may confound the results.

US Midwestern Metal Pickling Cohort

Beaumont et al. (1987) retrospectively followed 1,165 workers at three midwestern steel-manufacturing facilities. Subjects were employed for at least 6 months in a pickling-related job from 1940 to 1964. Mortality was followed through 1981 by using vital statistics from the Social Security Administration and Internal Revenue Service. From work-history records, industrial-hygiene and engineering records and surveys, and company personnel expertise, subjects were categorized according to what acids they were exposed to in their metal-pickling jobs: sulfuric acid only, sulfuric and other acids, or other acids only (all members of this category worked at a single factory). Nitric acid was identified as a component of “other acid” exposure (a situation that occurred at only one of the three plants). When the overall cohort was compared with the US population, lung cancer stood out as the only markedly increased cause of death (SMR 1.64, 95% CI 1.14–2.28); the risk of death related to diabetes was also increased (SMR 1.65, 95% CI 0.71–2.26). The lung-cancer increase was extreme for those who had worked only with “other acids”

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

(SMR 2.24). In an effort to control for smoking and other socioeconomic factors, a comparison was made with Allegheny County steelworkers—the Pennsylvania cohort whose pickling portion was reported on by Mazumdar et al. (1975)—but this required restricting the Midwestern cohort to those employed from 1950 to 1954. Lung cancer mortality was again most increased among those working exclusively with “other acids” (SMR 2.00, 95% CI 1.06–3.78). Although this subset of workers was exposed to acids other than nitric acid (such as hydrochloric, hydrofluoric, and hydrocyanic acids), the findings suggest that sulfuric acid may not be exclusively or primarily responsible for carcinogenic effects observed among those working with strong inorganic acids.

Steenland et al. (1988) examined a subset of 879 subjects from the Midwestern cohort in whom it could be determined whether laryngeal cancer had ever been diagnosed. Beaumont et al. (1987) found two deaths among all the pickling workers; this suggested an increase (SMR 1.93, 95% CI 0.23–6.99) for laryngeal cancer, which has 5-year survival of better than 50%. Steenland et al. (1988) found an additional seven diagnoses of laryngeal cancer (standard incidence ratio [SIR] 2.30; 9 observed cases vs 3.92 expected, with adjustment for smoking). The small number of cases precluded detailed analysis by acid-exposure group and it was not stated whether the 62% sulfuric acid-only, 22% mixed, and 16% “other-acids-only” partition of the full cohort was carried into the subset; but it was reported that four, three, and two of the cases, respectively, were in these categories.

Steenland and Beaumont (1989) followed up mortality in that cohort into 1986 and gathered individual smoking histories from those still living or next of kin. The findings for lung cancer remained increased (SMR 1.55, 95% CI 1.12–2.11), but adjustment for the smoking information dampened the increase (SMR 1.36, 95% CI 0.97–1.84). Results were not presented by the separate acid-exposure groups, so little insight was gained into any effects that might be due to nitric acid or the other nonsulfuric acids used in the pickling jobs.

Italian Chemical Plant Workers

Rapiti et al. (1997) examined occupational risk factors for cancer mortality in a cohort of 505 men employed from 1954 to 1970 in an Italian chemical plant. Vital status through June 1991 was obtained from registry offices. In compliance with a 1954 national law, workers exposed to particular chemicals were examined annually, and the employees’ work histories were kept with their medical records. Screening of those files revealed that 125 subjects had been engaged at some point during their employment in the production of acid mixtures that included sulfuric and nitric acids. Compared with regional causes of death, acid exposure was associated with increases stomach cancer (SMR 1.47, 90% CI 0.40–3.80), pancreatic cancer (SMR 1.69, 90% CI 0.09–8.04), lung cancer (SMR 1.62, 90% CI 0.81–2.92), non-Hodgkin’s lymphoma (SMR 4.17, 90% CI 0.04–19.7), and leukemia (SMR 1.79, 90% CI 0.09–8.47). The authors discussed the hypothesized association between laryngeal cancer and acid mixtures, but apparently no such deaths were observed in the entire cohort. The exposure circumstances in the plant where nitric acid was used in combination with sulfuric acid are of particular interest, but the small numbers of exposed cases resulted in extremely wide, largely uninformative confidence intervals (even at the 90% level).

Nitric Acid Production Cohort

A cohort of 287 male workers at a nitric acid production plant in Norway was studied by Hilt et al. (1985) through 1980 and followed up by Hilt et al. (1991) through 1988. The subjects were regularly exposed to asbestos in the period 1928–1980, but the researchers focused on workers exposed to asbestos before 1961 who had not died before 1953. The incidence of cancer

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

was calculated on the basis of data from the Norwegian Cancer Registry, which was thought to be comprehensive for cancer diagnosis for the period in question. Exposure to asbestos was assessed through occupational-history records and was the primary exposure of interest for the study. Although the plant workers were engaged in processes related to nitric acid production, no measurements of exposure to this compound were included in the studies. In all likelihood, the increased reported risks of lung cancer and pleural mesothelioma were driven by asbestos exposure. The studies were well-conducted but are of marginal utility for the purposes of this review (and particularly for evaluating respiratory cancers) because the exposure experience of the subjects is dominated by asbestos. The effects of nitric acid exposure were not studied specifically and cannot be inferred.

Case-Control Studies
Laryngeal Cancer

A study of laryngeal cancer performed by Zemla et al. (1987) comprised 328 cases of native and migrant workers in Upper Silesia who were located through the Institute of Oncology in Poland from 1980–1984 and 656 population controls. Self-reported histories of occupational hazards included exposure to vapors containing sulfuric, hydrochloric, and nitric acids. Exposure to acid vapors was associated with an increase in laryngeal cancer among natives (RR 0.57, 95% CI 0.07–2.06), immigrants (RR 4.50, 95% CI 2.06–8.54), and both together (RR 2.0, 95% CI 1.00–3.52). Since the statistics in the table did not appear to correspond with the observed number reported, the committee re-calculated the RR and CI. The numbers indicate that there is a big difference between the natives and the immigrants. However, the study is limited by the use of self-reported and broadly defined exposure-assessment methods.

Eisen et al. (1994) conducted a case-control study of laryngeal cancer among automobile workers exposed to machining fluids in the automobile industry. Qualitative data were also collected on exposure to acid mists (including nitric, phosphoric, and sulfuric acids) in two of the three plants studied. Exposure information was based on self-reports from long-term employees and industrial-hygiene records. Treated as a continuous variable, each year of acid mist exposure was not shown to increase risk of laryngeal cancer (OR 0.90, 95% CI 0.66–1.22).

De Stefani et al. (1998) studied 112 incident and histologically confirmed cases of laryngeal cancer at five hospitals in Montevideo from 1993 to 1995 in comparison with 509 controls with cancers not related to tobacco or alcohol use. Self-reported histories of exposure were gathered by questionnaire and addressed strong inorganic acids (defined as hydrochloric, nitric, or sulfuric acid). Risk of laryngeal cancer was increased with reported exposure to strong acid (OR 1.6, 95% CI 0.9–2.6), and a dose-response relation with years of exposure was suggested: subjects exposed for 1–20 years, OR 1.2, 95% CI 0.6–2.5, and subjects exposed for 20 years, OR 1.8, 95% CI 1.1–3.1. Synergism with heavy smoking (≥36 pack-years) was also demonstrated (OR 11.6, 95% CI 5.5–24.2).

In their case-control study of squamous cell carcinomas of the “upper gastrointestinal tract” diagnosed among Swedish men in 1988–1991, Gustavsson et al. (1998) reported on a set of 157 laryngeal-cancer cases compared with referents from the population registry matched on region and age group. Work histories and other personal information were gathered by nurses in structured in-person interviews. An occupational hygienist abstracted the extent of exposure to 17 occupational factors from the work histories; “acid mist” was one of them, but what specific acids were included was unstated. Exposure to acid mists was found to be associated with an increased risk of laryngeal cancer (OR 1.31, 95% CI 0.41–4.22).

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×
Multiple Myeloma

Morris et al. (1986) performed a case-control study of 698 cases of multiple myeloma from four Surveillance, Epidemiology, and End Results (SEER) registries in 1977–1981 with a population control group of 1,683. Exposure information was self-reported for 68% of the cases and 99% of the controls with family-member proxies providing data for deceased or ill subjects. Exposure to acids (including muriatic, hydrochloric, sulfuric, chromic, nitric, and acetic acids) was associated with an increased risk of multiple myeloma when analysis was limited to self-respondents (OR 1.5, 95% CI 0.8–2.8), but the effect was eliminated when proxy respondents were included (OR 1.0, 95% CI 0.6–1.9).

Non-Cancer Health Outcomes
Cardiovascular Effects

As described above, Mazumdar et al. (1975) followed the mortality of a cohort of Pennsylvania steelworkers employed through 1966. Selected “cardiovascular-renal diseases” were studied in more detail when overall increases were noted among the white workers. Addition of the requirement of having worked for at least 5 years in the plants to the previous criterion of having been employed in 1953 reduced the number of evaluated deaths from those causes to 6,839. The risk of death due to arteriosclerotic heart disease was increased for all the acid-related jobs except coating; the risk posed by batch pickling was especially increased (12 observed, 5.4 expected; RR 2.55, p<0.01). Coating, however, was the only acid-related job category that showed an increased rate of death from hypertensive heart disease (6 observed, 1.1 expected; RR 10.83; p<0.01). For vascular lesions of the central nervous system, sheet finishing (24 observed, 18.3 expected; RR 1.41) and stainless annealing (4 observed, 3.2 expected) showed slight increases.

Respiratory Effects

Three studies evaluated respiratory function among nitric acid plant workers. Kamat et al. (1984) reported increases in dyspnea and cough, chest pain, giddiness, and headaches associated with longer periods of work among 125 men at an Indian nitric acid plant. Kolhatkar et al. (1987) evaluated respiratory symptoms and functions in a study of 113 male workers exposed to nitric acid at two other plants in India and found some chronic restrictive lung changes after long-term occupational exposure. Hilt (1987) documented clinical examinations of 153 men from the cohort of Norwegian nitric acid production workers described above (Hilt et al. 1985, 1991); the subjects were exposed primarily to asbestos, so little can be inferred about the role of nitric acid.

Summary

On the basis of the committee’s review of the epidemiologic evidence, no available studies directly examined the association between exposure to nitric acid and long-term human health effects. Most studies were able only to investigate the health effects of nitric acid in combination with other strong inorganic acids, such as sulfuric acid, or other known carcinogens such as asbestos: that is, an independent assessment of nitric acid exposure was impossible because workers were exposed simultaneously to such mixtures. As a result, the health effects associated with exposure to nitric acid alone cannot be assessed.

Given the limitations of the body of evidence described above, it is interesting that what findings there are cluster mostly around respiratory cancers. The cohort studies on sheet and tin mill workers (Mazumdar et al. 1975), steel-pickling workers (Ahlborg et al. 1981; Beaumont et

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

al. 1987), and chemical-plant workers (Rapiti et al. 1997) found an increased risk of lung cancer among those exposed to mixtures of acids. Similarly, several cohort studies (Ahlborg et al. 1981; Eisen et al. 1994; Steenland et al. 1988) and case-control studies (De Stefani et al. 1998; Zemla et al. 1987) indicated an increased risk of laryngeal cancer with exposure to acid mists and strong acid mixtures. Not only could the effects of nitric acid not be separated from those of other agents, but the small samples resulted in relatively small numbers of observed cancers and in inadequate study power.

IARC (1992) included nitric acid in its review of strong inorganic acids for which the conclusion was that strong-inorganic-acid mists containing sulfuric acid are carcinogenic in humans. However, very little is known about the dosimetry of inhaled nitric acid. Nitric acid generally exists in air in the vapor state except in acid fogs. Although the high water solubility and existence in the vapor state suggests that it should undergo substantial removal in the upper respiratory tract, there is some evidence that inhaled vapor-phase nitric acid may be converted into or deposited on small particles in the humid atmosphere of the respiratory tract. That would facilitate its transport to and deposition in the deep lung (Chen and Schlesinger 1996). In contrast, the data supporting a role for sulfuric acid in occupational cancers of the larynx involved exposures to large acid droplets, which would deposit in the upper respiratory tract. Thus, because the form of nitric acid that may have been inhaled by service personnel is not known, an analogy cannot be drawn between the apparent carcinogenic effects of industrial exposures to sulfuric acid and any possible carcinogenic effects of Gulf War exposures to nitric acid.

Furthermore, the underlying mechanism thought to be responsible for the carcinogenicity of strong-inorganic-acid mists would require extensive chronic exposure, which would not be equivalent to a person’s being exposed to all of the few Scuds that may have disintegrated over troops during the Gulf War.

The available epidemiologic findings on cancer at other sites and on noncancer health outcomes are largely isolated data points generated in the course of investigating the potential of nitric acid or other strong inorganic acids as respiratory carcinogens.

Several toxicologic and controlled clinical studies have been performed with nitric acid vapors (Abraham et al. 1982; Aris et al. 1993; Beckett et al. 1995; Koenig et al. 1989; Mautz et al. 1995; Schlesinger et al. 1994). Whether those studies involved acute or repeated exposures, however, biologic endpoints were assayed within 24 hours of cessation of exposure. Thus, they do not add compelling information regarding persistent effects of exposure to nitric acid.

The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to nitric acid and lung, laryngeal, stomach, bladder, colon, pancreatic, or lymphopoietic cancers; melanoma; multiple myeloma; or mortality from cardiovascular diseases.

Table 9.6 provides the key findings reviewed by the committee.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

TABLE 9.6 Selected Epidemiologic Studies—Health Outcomes and Exposure to Nitric Acid

Reference

Study Population

Exposed Cases

Estimated Relative Risk

Respiratory Cancer (broken out below where Lung or Larynx was presented separately)

Cohort Studies

Mazumdar et al. 1975

Pennsylvania sheet and tin mill cohort (cancer of “respiratory organs”, ICD not specified)

 

 

 

Jobs with exposure to acid baths (containing sulfuric, hydrochloric, or phosphoric acid)

 

 

Batch pickling and sheet dryers

0

Continuous pickling and electric cleaning

0

Stainless annealing, pickling, and processing

2

3.33 (0.40–12.03)b

Coating

4

1.43 (0.39–3.66)b

Sheet finishing and shipping

19

1.27 (0.73–1.90)b

Tin finishing and shipping

2

0.56 (0.07–2.01)b

Ahlborg et al. 1981

Swedish metal-pickling cohort (respiratory tract cancers, ICD 160–163)

 

 

 

No latency

4

6.06 (1.65–15.52)b

>10 years latency

4

7.27 (1.98–18.62)b

Beaumont et al. 1987

Midwestern metal-pickling cohort

 

 

All types of acid exposure

37

1.63 (1.15–2.26)

Lung Cancer

Cohort Studies

Steenland and Beaumont 1989

Midwestern metal-pickling cohort (employed 1940–1964)

 

 

 

Mortality through 1986

 

 

 

All types acid exposure

41

1.55 (1.12–2.11)

 

Adjust for smoking

41

1.36 (0.97–1.84)

Beaumont et al. 1987

Mortality through 1981

 

 

All types of acid exposure

35

1.64 (1.14–2.28)a

 

Sulfuric acid only

19

1.39, p>0.05

Daily and ≥20 years since first employment

16

1.93, p<0.05

Sulfuric and other acids

7

1.92, p>0.05

Other acids only

9

2.24, p<0.05

Time since first employment

 

 

0.5–20 years

2

3.26, p>0.05

≥20 years

7

2.06, p>0.05

Only those employed 1950–1954)

 

 

vs US population

9

2.42 (1.11–4.61)

vs Allegheny County steelworkers

9

2.00 (1.06–3.78)

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk

Rapiti et al. 1997

Italian chemical-plant workers

 

 

Exposed to acid mixtures

8

1.62 (0.81–2.92)c

Laryngeal Cancer

Cohort Studies

Ahlborg et al. 1981

Swedish metal-pickling cohort

 

 

 

No latency

3

50.00 (10.32–146.17)b

 

>10 years latency

3

60.00 (12.38–175.40)b

Beaumont et al. 1987

Midwestern metal-pickling cohort

 

 

 

Mortality, all acid groups

2

1.93 (0.23–6.99)

Steenland et al. 1988

Incidence, all acid groups (two in “other acids”)

9

2.30 (1.05–4.36)a

 

≤5 years duration (one in “other acids”)

3

1.70 (0.35–4.95)a

 

>5 years duration (one in “other acids”)

6

2.76 (1.01–6.02)a

Case-Control Studies

Eisen et al. 1994

Nested case-control in cohort of automobile workers exposed to machining fluids

 

 

 

Years exposed to acid mist

na

0.90 (0.66–1.22)

Zemla et al. 1987

Residents of Upper Silesia, Poland

 

 

 

Exposed to vapor (including nitric acid)

11

2.00 (1.00–3.52)

Natives

2

0.57 (0.07–2.06)

Immigrants

9

4.50 (2.06–8.54)

De Stefani et al. 1998

Residents of Montevideo, Uruguay

 

 

 

Exposed to strong acids (including nitric acid)

46

1.6 (0.9–2.6)

 

1–20 years

12

1.2 (0.6–2.5)

 

≥21 years

34

1.8 (1.1–3.1)

Gustavsson et al. 1998

Swedish men

 

 

 

Exposed to acid mist

4

1.31 (0.41–4.22)

Esophageal Cancer

Case-Control Study

Parent et al. 2000

Montreal case-control study set

 

 

 

All histologic types

15

2.2 (1.2–4.3)

Exposure to sulfuric acid

 

 

Nonsubstantial

12

2.0 (1.0–4.0)

Substantial

3

4.1 (1.0–17.2)

Squamous cell carcinoma

10

2.8 (1.2–6.1)

Exposure to sulfuric acid

 

 

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk

 

Nonsubstantial

9

2.2 (1.2–6.3)

 

Substantial

1

3.1 (0.3–28.1)

Lymphopoietic Cancer

Cohort Studies

Mazumdar et al. 1975

Pennsylvania sheet and tin mill cohort

 

 

 

Jobs with exposure to acid baths (containing sulfuric, hydrochloric, or phosphoric acid)

 

 

 

Batch pickling and sheet dryers

0

Continuous pickling and electric cleaning

0

Stainless annealing, pickling, and processing

1

5.0 (0.13–27.85)b

Coating

0

Sheet finishing and shipping

0

Tin finishing and shipping

3

3.00 (0.62–8.77)b

Rapiti et al. 1997

Italian chemical-plant workers

 

 

 

Exposed to acid mixtures

2

1.87 (0.33–5.88)c

 

Non-Hodgkin’s lymphoma

1

4.17 (0.04–19.70)c

 

Leukemia

1

1.79 (0.09–8.47)c

Multiple Myeloma

Case-Control Study

Morris et al. 1986

Residents of four US states

 

 

 

Self-respondents and proxies

20

1.0 (0.6–1.9)

 

Self-respondents only

19

1.5 (0.8–2.8)

Non-Cancer Health Outcomes

Arteriosclerotic Heart Disease (Mortality)

Cohort Study

Mazumdar et al. 1975

Pennsylvania sheet and tin mill cohort (≥5 years)

 

 

 

Jobs with exposure to acid baths (containing sulfuric, hydrochloric, or phosphoric acid)

 

 

 

Batch pickling and sheet dryers

12

2.55 (1.15–3.88)a (p<0.01)

Continuous pickling and electric cleaning

8 (vs 6.9)

1.17

Stainless annealing, pickling, and processing

16 (vs 14.0)

1.16

Coating

12

0.66 (0.35–1.20)a

Sheet finishing and shipping

98

1.07 (0.86–1.29)a

Tin finishing and shipping

26

1.08 (0.69–1.56)a

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk

Hypertensive Heart Disease (Mortality)

Cohort Study

Mazumdar et al. 1975

Pennsylvania sheet and tin mill cohort (≥5 years)

 

 

 

Jobs with exposure to acid baths (containing sulfuric, hydrochloric, or phosphoric acid)

 

 

 

Batch pickling and sheet dryers

0

Continuous pickling and electric cleaning

0

Stainless annealing, pickling, and processing

1 (vs 0.5)

2.0

Coating

6 (vs 1.1)

10.83 (p<0.01)

Sheet finishing and shipping

1

0.26 (0.01–1.43)a

Tin finishing and shipping

0

Vascular Lesions of CNS (Mortality)

Cohort Study

Mazumdar et al. 1975

Pennsylvania sheet and tin mill cohort (≥5 years)

 

 

 

Jobs with exposure to acid baths (containing sulfuric, hydrochloric, or phosphoric acid)

 

 

 

Batch pickling and sheet dryers

0

Continuous pickling and electric cleaning

0

Stainless annealing, pickling, and processing

4 (vs 3.2)

1.25

Coating

3

0.75 (0.15–2.19)b

Sheet finishing and shipping

24

1.41 (0.84–1.95)a

Tin finishing and shipping

4

0.74 (0.21–1.97)a

Diabetes Mellitus (Mortality)

Cohort Study

Beaumont et al. 1987

Midwestern metal-pickling cohort

 

 

All types of acid exposure

8

1.65 (0.71–3.26)

NOTE: na=not available.

a95% CIs were calculated with standard methods from the observed and expected numbers presented in the original paper.

bRisk estimates and 95% CIs were calculated with standard methods from the observed and expected numbers presented in the original paper.

c90% CIs were reported.

Suggested Citation:"9 Hydrazines and Nitric Acid." Institute of Medicine. 2005. Gulf War and Health: Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. doi: 10.17226/11180.
×

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ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Profile for Hydrazines. Atlanta, GA: US Department of Health and Human Services, Public Health Service, ATSDR.


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Next: Appendix A: Conclusions from Gulf War and Health Volumes 1 and 2 »
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The third in a series of congressionally mandated reports on Gulf War veterans’ health, this volume evaluates the long-term, human health effects associated with exposure to selected environmental agents, pollutants, and synthetic chemical compounds believed to have been present during the Gulf War. The committee specifically evaluated the literature on hydrogen sulfide, combustion products, hydrazine and red fuming nitric acid. Both the epidemiologic and toxicologic literature were reviewed.

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